Carvajal Gonczi, Catalina Marysol (2020) Modulation of Helper T Cells by β2 Adrenergic Receptor Ligands in a PKA-Dependent Manner. PhD thesis, Concordia University.
Preview |
Text (application/pdf)
7MBCarvajal_PhD_S2021.pdf - Accepted Version |
Abstract
Abstract
Modulation of Helper T Cells by β2 Adrenergic Receptor Ligands in a PKA-Dependent Manner
Catalina Marysol Carvajal Gonczi, Ph.D
Concordia University, 2020
Background: T helper (Th) cells may attack self-tissues in susceptible people resulting in chronic autoimmune disease. A subtype of Th cells called Th17 cells are considered to be pro-inflammatory by secreting IL-17A cytokines. Discovering new drugs to suppress Th17 cells is a major goal for researchers. Ligands for the beta2-adrenergic receptor (β2AR, encoded by ADRB2) are known to suppress pro-inflammatory Th1 cells, but their effects on Th17 cells have not been widely studied. I studied the effect of β2AR ligands on Th1 and Th17 cells and determined the influence of common polymorphisms ADRB2. The goal was to discover a potential new immunomodulatory drug to explore as autoimmune disease treatment.
Methods: Human immune cells from healthy participants obtained after informed consent were tested in vitro. The samples were activated with T cell-specific activator, and cytokines were measured. The in vitro drug treatments included a β2AR specific agonist (terbutaline), an inverse-agonist (nebivolol), a β2AR specific antagonist (ICI 118-551), cAMP analogues that promote or inhibit the pathway, PKA inhibitor and phosphodiesterase inhibitor (which raises cAMP levels). Known polymorphisms were determined by sequencing ADRB2 from samples.
Results: Primary human Th17 cells expressed the β2AR. Terbutaline augmented IL-17A in activated peripheral blood mononuclear cells and Th17 cells, while IFNγ was concurrently inhibited. Proliferation was not inhibited, rather, an increase was observed in the presence of terbutaline. Using PKA inhibitors and cAMP analogues, it was shown that IL-17A was augmented by terbutaline in a cAMP and PKA-dependent manner. Terbutaline promoted phosphorylation of CREB. Nebivolol inhibited both IL-17A and IFNγ in activated peripheral blood mononuclear cells and Th cells. In samples where ADRB2 was homozygous for Arg16, terbutaline inhibited IFNγ but did not augment IL-17A. Nebivolol inhibited both cytokines regardless of the polymorphism of the ADRB2.
Relevance: These results are novel because the inverse-agonist of β2AR has not been widely studied as an immunomodulator. The cell signalling results demonstrated that Th17 cells respond differently than other Th cells to cAMP-PKA pathway, which suggests the use of other drugs with inverse-agonist properties. Discovering new immunomodulatory drugs will give doctors more options to treat autoimmune patients.
Divisions: | Concordia University > Faculty of Arts and Science > Biology |
---|---|
Item Type: | Thesis (PhD) |
Authors: | Carvajal Gonczi, Catalina Marysol |
Institution: | Concordia University |
Degree Name: | Ph. D. |
Program: | Biology |
Date: | July 2020 |
Thesis Supervisor(s): | Darlington, Peter |
ID Code: | 987967 |
Deposited By: | Catalina Marysol Carvajal |
Deposited On: | 29 Jun 2021 21:00 |
Last Modified: | 29 Jun 2021 21:00 |
References:
Reference1. Wacker D, Fenalti G, Brown MA, Katritch V, Abagyan R, Cherezov V, et al. Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J Am Chem Soc. 2010;132(33):11443–5.
2. Erickson CE, Gul R, Blessing CP, Nguyen J, Liu T, Pulakat L, et al. The beta-blocker Nebivolol Is a GRK/beta-arrestin biased agonist. PloS One. 2013 Aug 20;8(8):e71980.
3. Beng H, Zhang H, Jayachandra R, Li J, Wu J, Tan W. Enantioselective resolution of Rac-terbutaline and evaluation of optically pure R-terbutaline hydrochloride as an efficient anti-asthmatic drug. Chirality. 2018;30(6):759–68.
4. Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol. 2010 Feb 1;125(2):S33–40.
5. Blum JS, Wearsch PA, Cresswell P. Pathways of Antigen Processing. Annu Rev Immunol. 2013 Mar 21;31(1):443–73.
6. Ribas A. Adaptive Immune Resistance: How Cancer Protects from Immune Attack. Cancer Discov. 2015 Sep;5(9):915–9.
7. Rojas M, Restrepo-Jiménez P, Monsalve DM, Pacheco Y, Acosta-Ampudia Y, Ramírez-Santana C, et al. Molecular mimicry and autoimmunity. J Autoimmun. 2018 Dec 1;95:100–23.
8. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004 Oct;5(10):987–95.
9. Mohan JF, Unanue ER. A novel pathway of presentation by class II-MHC molecules involving peptides or denatured proteins important in autoimmunity. Mol Immunol. 2013 Sep;55(2):166–8.
10. Metzger TC, Anderson MS. Control of central and peripheral tolerance by Aire. Immunol Rev. 2011;241(1):89–103.
11. Yatim KM, Lakkis FG. A Brief Journey through the Immune System. Clin J Am Soc Nephrol CJASN. 2015 Jul 7;10(7):1274–81.
12. Mariuzza RA, Agnihotri P, Orban J. The structural basis of T-cell receptor (TCR) activation: An enduring enigma. J Biol Chem. 2020 Jan 24;295(4):914–25.
13. Kisielow J, Obermair F-J, Kopf M. Deciphering CD4+ T cell specificity using novel MHC-TCR chimeric receptors. Nat Immunol. 2019;20(5):652–62.
14. Takaba H, Takayanagi H. The Mechanisms of T Cell Selection in the Thymus. Trends Immunol. 2017 Nov 1;38(11):805–16.
15. Courtney AH, Lo W-L, Weiss A. TCR SIGNALING: MECHANISMS OF INITIATION AND PROPAGATION. Trends Biochem Sci. 2018 Feb;43(2):108–23.
16. Horejsí V. Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling. Immunol Lett. 2004 Mar 29;92(1–2):43–9.
17. Wang X, Chuang H-C, Li J-P, Tan T-H. Regulation of PKC-θ function by phosphorylation in T cell receptor signaling. Front Immunol. 2012;3:197.
18. Mosenden R, Taskén K. Cyclic AMP-mediated immune regulation--overview of mechanisms of action in T cells. Cell Signal. 2011 Jun;23(6):1009–16.
19. Hynes TR, Yost EA, Yost SM, Hartle CM, Ott BJ, Berlot CH. Inhibition of Galphas/cAMP Signaling Decreases TCR-Stimulated IL-2 transcription in CD4(+) T Helper Cells. J Mol Signal. 2015 Jul 6;10:2-2187-10–2.
20. Tokoyoda K, Tsujikawa K, Matsushita H, Ono Y, Hayashi T, Harada Y, et al. Up-regulation of IL-4 production by the activated cAMP/cAMP-dependent protein kinase (protein kinase A) pathway in CD3/CD28-stimulated naive T cells. Int Immunol. 2004;16(5):643–53.
21. Acuto O, Michel F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol. 2003 Dec;3(12):939–51.
22. Smith-Garvin J, Koretzky GA, Jordan MS. T Cell Activation. Annu Rev Immunol. 2009;27(Journal Article):591–619.
23. Broere F, van Eden W. T Cell Subsets and T Cell-Mediated Immunity. In: Parnham MJ, Nijkamp FP, Rossi AG, editors. Nijkamp and Parnham’s Principles of Immunopharmacology. Cham: Springer International Publishing; 2019. p. 23–35.
24. Burr JS, Savage ND, Messah GE, Kimzey SL, Shaw AS, Arch RH, et al. Cutting edge: distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL. J Immunol Baltim Md 1950. 2001 May 1;166(9):5331–5.
25. Orozco Valencia A, Camargo Knirsch M, Suavinho Ferro E, Antonio Stephano M. Interleukin-2 as immunotherapeutic in the autoimmune diseases. Int Immunopharmacol. 2020 Apr 1;81:106296.
26. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Helper T Cells and Lymphocyte Activation. Mol Biol Cell 4th Ed. 2002;
27. Matzinger P. The danger model: a renewed sense of self. Science. 2002 Apr 12;296(5566):301–5.
28. Abrahamsen H, Baillie G, Ngai J, Vang T, Nika K, Ruppelt A, et al. TCR- and CD28-mediated recruitment of phosphodiesterase 4 to lipid rafts potentiates TCR signaling. J Immunol. 2004;173(8):4847–58.
29. Conche C, Boulla G, Trautmann A, Randriamampita C. T cell adhesion primes antigen receptor-induced calcium responses through a transient rise in adenosine 3’,5’-cyclic monophosphate. Immunity. 2009;30(1):33–43.
30. Varshney P, Yadav V, Saini N. Lipid rafts in immune signalling: current progress and future perspective. Immunology. 2016 Sep;149(1):13–24.
31. Yang X, Chatterjee V, Ma Y, Zheng E, Yuan SY. Protein Palmitoylation in Leukocyte Signaling and Function. Front Cell Dev Biol. 2020;8:600368.
32. Oh P, Schnitzer JE. Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default. Mol Biol Cell. 2001 Mar;12(3):685–98.
33. Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skalhegg BS, et al. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med. 2001;193(4):497–507.
34. Davidson D, Bakinowski M, Thomas ML, Horejsi V, Veillette A. Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Mol Cell Biol. 2003 Mar;23(6):2017–28.
35. Arp J, Kirchhof MG, Baroja ML, Nazarian SH, Chau TA, Strathdee CA, et al. Regulation of T-cell activation by phosphodiesterase 4B2 requires its dynamic redistribution during immunological synapse formation. Mol Cell Biol. 2003;23(22):8042–57.
36. Heijink IH, Vellenga E, Borger P, Postma DS, Monchy JGR de, Kauffman HF. Polarized Th1 and Th2 cells are less responsive to negative feedback by receptors coupled to the AC/cAMP system compared to freshly isolated T cells. Br J Pharmacol. 2003;138(8):1441–50.
37. Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function. J Immunol Baltim Md 1950. 2010 Dec 1;185(11):6413–9.
38. Hughes-Fulford M, Sugano E, Schopper T, Li CF, Boonyaratanakornkit JB, Cogoli A. Early immune response and regulation of IL-2 receptor subunits. Cell Signal. 2005;17(9):1111–24.
39. Barton K, Muthusamy N, Chanyangam M, Fischer C, Clendenin C, Leiden JM. Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB. Nature. 1996;379(6560):81–5.
40. Zhang F, Rincon M, Flavell RA, Aune TM. Defective Th function induced by a dominant-negative cAMP response element binding protein mutation is reversed by Bcl-2. J Immunol Baltim Md 1950. 2000;165(4):1762–70.
41. Wang X, Ni L, Chang D, Lu H, Jiang Y, Kim BS, et al. Cyclic AMP-Responsive Element-Binding Protein (CREB) is Critical in Autoimmunity by Promoting Th17 but Inhibiting Treg Cell Differentiation. EBioMedicine. 2017;25(Journal Article):165–74.
42. Hernandez JB, Chang C, LeBlanc M, Grimm D, Le Lay J, Kaestner KH, et al. The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. Nat Commun. 2015 Jun 2;6(1):7216.
43. Hammitzsch A, Tallant C, Fedorov O, O’Mahony A, Brennan PE, Hay DA, et al. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci. 2015 Aug 25;112(34):10768–73.
44. Aharoni R, Globerman R, Eilam R, Brenner O, Arnon R. Titration of myelin oligodendrocyte glycoprotein (MOG) - Induced experimental autoimmune encephalomyelitis (EAE) model. J Neurosci Methods. 2020 Nov 12;108999.
45. Kunkl M, Frascolla S, Amormino C, Volpe E, Tuosto L. T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis. Cells. 2020 Feb 19;9(2).
46. Sant AJ, Richards KA, Nayak J. Distinct and complementary roles of CD4 T cells in protective immunity to influenza virus. Curr Opin Immunol. 2018;53:13–21.
47. Spiering MJ. Primer on the Immune System. Alcohol Res Curr Rev. 2015;37(2):171–5.
48. Anstead MI, Hunt TA, Carlson SL, Burki NK. Variability of peripheral blood lymphocyte beta-2-adrenergic receptor density in humans. Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 1):990–2.
49. Hayday AC. γδ T Cell Update: Adaptate Orchestrators of Immune Surveillance. J Immunol. 2019 Jul 15;203(2):311–20.
50. Caccamo N, La Mendola C, Orlando V, Meraviglia S, Todaro M, Stassi G, et al. Differentiation, phenotype, and function of interleukin-17–producing human Vγ9Vδ2 T cells. Blood. 2011 Jul 7;118(1):129–38.
51. Campbell JJ, Qin S, Unutmaz D, Soler D, Murphy KE, Hodge MR, et al. Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol Baltim Md 1950. 2001 Jun 1;166(11):6477–82.
52. Santos LS, Sgnotto F da R, Sousa TR, Orfali RL, Aoki V, Duarte AJ da S, et al. IgG from atopic dermatitis patients induces non-atopic infant thymic invariant natural killer T (iNKT) cells to produce IL-4, IL-17, and IL-10. Int J Dermatol. 2020 Mar;59(3):359–64.
53. Jahng AW, Maricic I, Pedersen B, Burdin N, Naidenko O, Kronenberg M, et al. Activation of Natural Killer T Cells Potentiates or Prevents Experimental Autoimmune Encephalomyelitis. J Exp Med. 2001 Dec 17;194(12):1789–99.
54. Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of ctla-4 function. Annu Rev Immunol. 2006 Mar 21;24(1):65–97.
55. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995 Nov 10;270(5238):985–8.
56. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995 Nov;3(5):541–7.
57. Klocke K, Sakaguchi S, Holmdahl R, Wing K. Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Proc Natl Acad Sci. 2016 Apr 26;113(17):E2383–92.
58. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal-dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014 Dec;20(12):1410–6.
59. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142(6):1932–46.
60. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed Death-1 Ligand 1 Interacts Specifically with the B7-1 Costimulatory Molecule to Inhibit T Cell Responses. Immunity. 2007 Jul 27;27(1):111–22.
61. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001 Mar;2(3):261–8.
62. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol Baltim Md 1950. 2004 Jul 15;173(2):945–54.
63. Huang P-W, Chang JW-C. Immune checkpoint inhibitors win the 2018 Nobel Prize. Biomed J. 2019 Oct;42(5):299–306.
64. Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. J Cell Physiol. 2019;234(6):8509–21.
65. Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N, et al. Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3. J Exp Med. 2003 Dec 15;198(12):1875–86.
66. Barsheshet Y, Wildbaum G, Levy E, Vitenshtein A, Akinseye C, Griggs J, et al. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci. 2017 Jun 6;114(23):6086–91.
67. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells. Nat Immunol. 2003 Apr;4(4):330–6.
68. Huber S, Gagliani N, Esplugues E, O’Connor W, Huber FJ, Chaudhry A, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3− and Foxp3+ regulatory CD4+ T cells in an interleukin-10 dependent manner. Immunity. 2011 Apr 22;34(4):554–65.
69. Yamaguchi T, Wing JB, Sakaguchi S. Two modes of immune suppression by Foxp3+ regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol. 2011 Dec 1;23(6):424–30.
70. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007 Oct;27(4):635–46.
71. Godfrey VL, Wilkinson JE, Rinchik EM, Russell LB. Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5528–32.
72. Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. 2006 Jun 1;116(6):1713–22.
73. Gutiérrez-Vázquez C, Quintana FJ. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity. 2018 Jan 16;48(1):19–33.
74. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld J-C, et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008 May 1;453(7191):106–9.
75. Saravia J, Chapman NM, Chi H. Helper T cell differentiation. Cell Mol Immunol. 2019;16(7):634–43.
76. Szabo SJ, Dighe AS, Gubler U, Murphy KM. Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med. 1997 Mar 3;185(5):817–24.
77. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000 Mar 17;100(6):655–69.
78. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008 Jan;28(1):29–39.
79. Yamamoto J, Adachi Y, Onoue Y, Adachi YS, Okabe Y, Itazawa T, et al. Differential expression of the chemokine receptors by the Th1- and Th2-type effect or populations within circulating CD4+ T cells. J Leukoc Biol. 2000;68(4):568–74.
80. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature. 1996 Jul 11;382(6587):174–7.
81. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci J Virtual Libr. 2008 Jan 1;13:453–61.
82. Dardalhon V, Korn T, Kuchroo VK, Anderson AC. Role of Th1 and Th17 cells in organ-specific autoimmunity. J Autoimmun. 2008;31(3):252–6.
83. Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 2018 Sep;18(9):545–58.
84. Goldszmid RS, Caspar P, Rivollier A, White S, Dzutsev A, Hieny S, et al. NK cell-derived interferon-γ orchestrates the cellular dynamics and differentiation of monocytes into inflammatory dendritic cells at the site of infection. Immunity. 2012 Jun 29;36(6):1047–59.
85. Levy DE, Garcı́a-Sastre A. The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion. Cytokine Growth Factor Rev. 2001 Jun 1;12(2):143–56.
86. Nicolet BP, Guislain A, Alphen FPJ van, Gomez-Eerland R, Schumacher TNM, Biggelaar M van den, et al. CD29 identifies IFN-γ–producing human CD8+ T cells with an increased cytotoxic potential. Proc Natl Acad Sci. 2020 Mar 24;117(12):6686–96.
87. Bae HR, Leung PSC, Hodge DL, Fenimore JM, Jeon S-M, Thovarai V, et al. Multi-omics: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases. J Autoimmun. 2020 Jul;111:102436.
88. Gadotti AC, de Castro Deus M, Telles JP, Wind R, Goes M, Garcia Charello Ossoski R, et al. IFN-γ is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection. Virus Res. 2020 Nov;289:198171.
89. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997 May 16;89(4):587–96.
90. Morimoto Y, Bian Y, Gao P, Yashiro‐Ohtani Y, Zhou X-Y, Ono S, et al. Induction of surface CCR4 and its functionality in mouse Th2 cells is regulated differently during Th2 development. J Leukoc Biol. 2005;78(3):753–61.
91. Deo SS, Mistry KJ, Kakade AM, Niphadkar PV. Role played by Th2 type cytokines in IgE mediated allergy and asthma. Lung India Off Organ Indian Chest Soc. 2010;27(2):66–71.
92. Guo L, Huang Y, Chen X, Hu-Li J, Urban JF, Paul WE. Innate immunological function of T H 2 cells in vivo. Nat Immunol. 2015 Oct;16(10):1051–9.
93. Goswami R, Jabeen R, Yagi R, Pham D, Zhu J, Goenka S, et al. STAT6-Dependent Regulation of Th9 Development. J Immunol. 2012 Feb 1;188(3):968–75.
94. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, et al. Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008 Dec;9(12):1341–6.
95. Kara EE, Comerford I, Bastow CR, Fenix KA, Litchfield W, Handel TM, et al. Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites. J Immunol Baltim Md 1950. 2013 Aug 1;191(3):1110–7.
96. Putheti P, Awasthi A, Popoola J, Gao W, Strom TB. Human CD4+ Memory T Cells Can Become CD4+IL-9+ T Cells. PLOS ONE. 2010 Jan 14;5(1):e8706.
97. Petit-Frere C, Dugas B, Braquet P, Mencia-Huerta JM. Interleukin-9 potentiates the interleukin-4-induced IgE and IgG1 release from murine B lymphocytes. Immunology. 1993 May;79(1):146–51.
98. Méndez-Enríquez E, Hallgren J. Mast Cells and Their Progenitors in Allergic Asthma. Front Immunol. 2019;10:821.
99. Sehra S, Yao W, Nguyen ET, Glosson-Byers NL, Akhtar N, Zhou B, et al. TH9 cells are required for tissue mast cell accumulation during allergic inflammation. J Allergy Clin Immunol. 2015 Aug 1;136(2):433-440.e1.
100. Reitz M, Hartmann W, Rüdiger N, Orinska Z, Brunn M-L, Breloer M. Interleukin-9 promotes early mast cell-mediated expulsion of Strongyloides ratti but is dispensable for generation of protective memory. Sci Rep. 2018 Jun 5;8(1):8636.
101. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009 Jan 16;30(1):92–107.
102. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000 Nov;13(5):715–25.
103. Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010 May 28;32(5):605–15.
104. Yang XP, Ghoreschi K, Steward-Tharp SM, Rodriguez-Canales J, Zhu J, Grainger JR, et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol. 2011;12(3):247–54.
105. Gulen MF, Bulek K, Xiao H, Yu M, Gao J, Sun L, et al. Inactivation of the enzyme GSK3α by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates Interleukin-1-induced Th17 cell maintenance. Immunity. 2012 Nov 16;37(5):800–12.
106. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells. Cell. 2006 Sep 22;126(6):1121–33.
107. Singh SP, Zhang HH, Foley JF, Hedrick MN, Farber JM. Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. J Immunol. 2008;180(1):214–21.
108. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13(10):1173–5.
109. Liu H, Rohowsky-Kochan C. Regulation of IL-17 in Human CCR6+ Effector Memory T Cells. J Immunol. 2008 Jun 15;180(12):7948–57.
110. Sałkowska A, Karaś K, Karwaciak I, Walczak-Drzewiecka A, Krawczyk M, Sobalska-Kwapis M, et al. Identification of Novel Molecular Markers of Human Th17 Cells. Cells. 2020 Jul 3;9(7).
111. Montgomery CP, Daniels M, Zhao F, Alegre M-L, Chong AS, Daum RS. Protective Immunity against Recurrent Staphylococcus aureus Skin Infection Requires Antibody and Interleukin-17A. Infect Immun. 2014 May;82(5):2125–34.
112. Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of Interleukin-17A for Systemic Anti-Candida albicans Host Defense in Mice. J Infect Dis. 2004 Aug 1;190(3):624–31.
113. Borbón TY, Scorza BM, Clay GM, Lima Nobre de Queiroz F, Sariol AJ, Bowen JL, et al. Coinfection with Leishmania major and Staphylococcus aureus enhances the pathologic responses to both microbes through a pathway involving IL-17A. PLoS Negl Trop Dis. 2019 May;13(5):e0007247.
114. Gaffen SL, Moutsopoulos NM. Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity. Sci Immunol. 2020 Jan 3;5(43).
115. Liang SC, Long AJ, Bennett F, Whitters MJ, Karim R, Collins M, et al. An IL-17F/A Heterodimer Protein Is Produced by Mouse Th17 Cells and Induces Airway Neutrophil Recruitment. J Immunol. 2007 Dec 1;179(11):7791–9.
116. Huppert J, Closhen D, Croxford A, White R, Kulig P, Pietrowski E, et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J. 2010;24(4):1023–34.
117. Muranski P, Restifo NP. Essentials of Th17 cell commitment and plasticity. Blood. 2013;121(13):2402–14.
118. Darlington PJ, Stopnicki B, Touil T, Doucet J-S, Fawaz L, Roberts ME, et al. Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis. Front Immunol. 2018 May 7;9.
119. Yazdani MR, Khosropanah S, Doroudchi M. Interleukin-17 production by CD4+CD45RO+Foxp3+ T cells in peripheral blood of patients with atherosclerosis. Arch Med Sci Atheroscler Dis. 2019 Aug 26;4:e215–24.
120. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009 Aug;10(8):857–63.
121. Plank MW, Kaiko GE, Maltby S, Weaver J, Tay HL, Shen W, et al. Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity. J Immunol. 2017 Mar 1;198(5):2182–90.
122. Sabat R, Ouyang W, Wolk K. Therapeutic opportunities of the IL-22–IL-22R1 system. Nat Rev Drug Discov. 2014 Jan;13(1):21–38.
123. Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 Increases the Innate Immunity of Tissues. Immunity. 2004 Aug 1;21(2):241–54.
124. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008 Feb 1;118(2):534–44.
125. Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B, et al. Human Th17 Cells Comprise Heterogeneous Subsets Including IFN-γ–Producing Cells with Distinct Properties from the Th1 Lineage. J Immunol. 2010 Jul 1;185(1):679–87.
126. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8(6):639–46.
127. van Langelaar J, van der Vuurst de Vries RM, Janssen M, Wierenga-Wolf AF, Spilt IM, Siepman TA, et al. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention. Brain J Neurol. 2018 01;141(5):1334–49.
128. Noster R, Riedel R, Mashreghi M-F, Radbruch H, Harms L, Haftmann C, et al. IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci Transl Med. 2014 Jun 18;6(241):241ra80.
129. Bryson BD, Rosebrock TR, Tafesse FG, Itoh CY, Nibasumba A, Babunovic GH, et al. Heterogeneous GM-CSF signaling in macrophages is associated with control of Mycobacterium tuberculosis. Nat Commun. 2019 May 27;10(1):2329.
130. Papp KA, Gooderham M, Jenkins R, Vender R, Szepietowski JC, Wagner T, et al. Granulocyte–macrophage colony-stimulating factor (GM-CSF) as a therapeutic target in psoriasis: randomized, controlled investigation using namilumab, a specific human anti-GM-CSF monoclonal antibody. Br J Dermatol. 2019;180(6):1352–60.
131. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123–32.
132. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol. 2007 Feb;8(2):145–53.
133. Yu C-R, Mahdi RM, Ebong S, Vistica BP, Chen J, Guo Y, et al. Cell Proliferation and STAT6 Pathways Are Negatively Regulated in T Cells by STAT1 and Suppressors of Cytokine Signaling. J Immunol. 2004 Jul 15;173(2):737–46.
134. Hoeve MA, Savage NDL, de Boer T, Langenberg DML, de Waal Malefyt R, Ottenhoff THM, et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol. 2006 Mar;36(3):661–70.
135. O’Connor W, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, et al. A protective function for interleukin 17A in T cell–mediated intestinal inflammation. Nat Immunol. 2009 Jun;10(6):603–9.
136. Ionescu L, Urschel S. Memory B Cells and Long-lived Plasma Cells. Transplantation. 2019;103(5):890–8.
137. Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM. T cell responses: naïve to memory and everything in between. Adv Physiol Educ. 2013;37(4):273–83.
138. McGeachy MJ. Th17 memory cells: live long and proliferate. J Leukoc Biol. 2013 Nov;94(5):921–6.
139. Brummelman J, Pilipow K, Lugli E. The Single-Cell Phenotypic Identity of Human CD8+ and CD4+ T Cells. Int Rev Cell Mol Biol. 2018;341:63–124.
140. Kryczek I, Zhao E, Liu Y, Wang Y, Vatan L, Szeliga W, et al. Human TH17 Cells Are Long-Lived Effector Memory Cells. Sci Transl Med. 2011 Oct 12;3(104):104ra100.
141. Bonilla FA. Vaccines in Patients with Primary Immune Deficiency. Immunol Allergy Clin North Am. 2020 Aug;40(3):421–35.
142. Valenzuela RM, Kaufman M, Balashov KE, Ito K, Buyske S, Dhib-Jalbut S. Predictive cytokine biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis. J Neuroimmunol. 2016 15;300:59–65.
143. Sandquist I, Kolls J. Update on regulation and effector functions of Th17 cells. F1000Research. 2018 Feb 19;7.
144. Ouyang W, Kolls JK, Zheng Y. The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation. Immunity. 2008;28(4):454–67.
145. Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev. 2008;223(Journal Article):87–113.
146. Jin W, Dong C. IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect. 2013 06;2(9):e60.
147. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2004;201(2):233–40.
148. Jäger A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17 and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol. 2009 Dec 1;183(11):7169–77.
149. Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM. IL-12– and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med. 2008 Jul 7;205(7):1535–41.
150. Domingues HS, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G. Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PloS One. 2010 Nov 29;5(11):e15531.
151. Prajeeth CK, Löhr K, Floess S, Zimmermann J, Ulrich R, Gudi V, et al. Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. Brain Behav Immun. 2014 Mar;37:248–59.
152. Setiadi AF, Abbas AR, Jeet S, Wong K, Bischof A, Peng I, et al. IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis. J Neuroimmunol. 2019 Jul 15;332:147–54.
153. Brambilla R. The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol (Berl). 2019;137(5):757–83.
154. Murphy AC, Lalor SJ, Lynch MA, Mills KHG. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. 2010 May;24(4):641–51.
155. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, et al. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999;42(5):963–70.
156. Shahrara S, Pickens SR, Dorfleutner A, Pope RM. IL-17 Induces Monocyte Migration in Rheumatoid Arthritis. J Immunol. 2009 Mar 15;182(6):3884–91.
157. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol Baltim Md 1950. 2006;177(1):566–73.
158. Hofstetter HH, Ibrahim SM, Koczan D, Kruse N, Weishaupt A, Toyka KV, et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol. 2005 Oct;237(2):123–30.
159. Koenders MI, Lubberts E, Oppers-Walgreen B, van den Bersselaar L, Helsen MM, Di Padova FE, et al. Blocking of Interleukin-17 during Reactivation of Experimental Arthritis Prevents Joint Inflammation and Bone Erosion by Decreasing RANKL and Interleukin-1. Am J Pathol. 2005 Jul 1;167(1):141–9.
160. Bush KA, Farmer KM, Walker JS, Kirkham BW. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum. 2002 Mar;46(3):802–5.
161. Sanford M, McKeage K. Secukinumab: First Global Approval. Drugs. 2015 Feb 1;75(3):329–38.
162. Havrdová E, Belova A, Goloborodko A, Tisserant A, Wright A, Wallstroem E, et al. Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study. J Neurol. 2016 Jul 1;263(7):1287–95.
163. Skepner J, Ramesh R, Trocha M, Schmidt D, Baloglu E, Lobera M, et al. Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo. J Immunol. 2014 Mar 15;192(6):2564–75.
164. Yang J, Sundrud MS, Skepner J, Yamagata T. Targeting Th17 cells in autoimmune diseases. Trends Pharmacol Sci. 2014 Oct 1;35(10):493–500.
165. Huh JR, Leung MWL, Huang P, Ryan DA, Krout MR, Malapaka RRV, et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature. 2011 Apr 28;472(7344):486–90.
166. Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic Acid Suppresses Interleukin-17 (IL-17) Production by Selectively Antagonizing the Function of RORγt Protein. J Biol Chem. 2011 Jul 1;286(26):22707–10.
167. Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, et al. Suppression of TH17 Differentiation and Autoimmunity by a Synthetic ROR Ligand. Nature. 2011 Apr 28;472(7344):491–4.
168. Dominguez-Villar M, Raddassi K, Danielsen AC, Guarnaccia J, Hafler DA. Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo. 49. 2019 Jan 1;
169. Rommer PS, Milo R, Han MH, Satyanarayan S, Sellner J, Hauer L, et al. Immunological Aspects of Approved MS Therapeutics. Front Immunol. 2019;10.
170. Rafei M, Campeau PM, Aguilar-Mahecha A, Buchanan M, Williams P, Birman E, et al. Mesenchymal Stromal Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Inhibiting CD4 Th17 T Cells in a CC Chemokine Ligand 2-Dependent Manner. J Immunol. 2009 May 15;182(10):5994–6002.
171. Darlington PJ, Boivin MN, Renoux C, Francois M, Galipeau J, Freedman MS, et al. Reciprocal Th1 and Th17 regulation by mesenchymal stem cells: Implication for multiple sclerosis. Ann Neurol. 2010 Oct;68(4):540–5.
172. Rozenberg A, Rezk A, Boivin MN, Darlington PJ, Nyirenda M, Li R, et al. Human Mesenchymal Stem Cells Impact Th17 and Th1 Responses Through a Prostaglandin E2 and Myeloid-Dependent Mechanism. Stem Cells Transl Med. 2016;(Journal Article).
173. Darlington PJ, Touil T, Doucet JS, Gaucher D, Zeidan J, Gauchat D, et al. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Ann Neurol. 2013;73(3):341–54.
174. Bourdette D. Rituximab for treating multiple sclerosis: Off-label but on target. Neurology. 2016 15;87(20):2070–1.
175. Berntsson SG, Kristoffersson A, Boström I, Feresiadou A, Burman J, Landtblom AM. Rapidly increasing off-label use of rituximab in multiple sclerosis in Sweden - Outlier or predecessor? Acta Neurol Scand. 2018 Oct;138(4):327–31.
176. Hellgren J, Risedal A, Källén K. Rituximab in multiple sclerosis at general hospital level. Acta Neurol Scand. 2020 Jun;141(6):491–9.
177. Davies M, Wilton L, Shakir S. Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study. Drug Saf. 2013 Apr;36(4):237–46.
178. Beiske GAG, Holmøy T, Beiske AG, Johannessen SI, Johannessen Landmark C. Antiepileptic and Antidepressive Polypharmacy in Patients with Multiple Sclerosis. Mult Scler Int. 2015;2015.
179. Khoury SJ, Healy BC, Kivisakk P, Viglietta V, Egorova S, Guttmann CR, et al. A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. Arch Neurol. 2010;67(9):1055–61.
180. Hartung DM, Bourdette DN, Ahmed SM, Whitham RH. The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail? Neurology. 2015 May 26;84(21):2185–92.
181. Nebivolol Price of 65 Brands / Trade Names | Medindia [Internet]. [cited 2020 Nov 30]. Available from: https://www.medindia.net/drug-price/nebivolol.htm
182. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000 Dec;52(4):595–638.
183. Livnat S, Felten SY, Carlson SL, Bellinger DL, Felten DL. Involvement of peripheral and central catecholamine systems in neural-immune interactions. Spec Issue Neuroimmunomodulation. 1985;10(1):5–30.
184. Felten DL, Ackerman KD, Wiegand SJ, Felten SY. Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. J Neurosci Res. 1987;18(1):28–36, 118–21.
185. Felten SY, Olschowka J. Noradrenergic sympathetic innervation of the spleen: II. Tyrosine hydroxylase (TH)-positive nerve terminals form synapticlike contacts on lymphocytes in the splenic white pulp. J Neurosci Res. 1987;18(1):37–48.
186. Kraal G. Cells in the marginal zone of the spleen. Int Rev Cytol. 1992;132:31–74.
187. Straub RH, Wiest R, Strauch UG, Härle P, Schölmerich J. The role of the sympathetic nervous system in intestinal inflammation. Gut. 2006 Nov;55(11):1640–9.
188. Kohm AP, Tang Y, Sanders VM, Jones SB. Activation of Antigen-Specific CD4+ Th2 Cells and B Cells In Vivo Increases Norepinephrine Release in the Spleen and Bone Marrow. J Immunol. 2000 Jul 15;165(2):725–33.
189. Kolb P, Rosenbaum DM, Irwin JJ, Fung JJ, Kobilka BK, Shoichet BK. Structure-based discovery of beta2-adrenergic receptor ligands. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6843–8.
190. Weis WI, Kobilka BK. The Molecular Basis of G Protein–Coupled Receptor Activation. Annu Rev Biochem. 2018 Jun 20;87:897–919.
191. Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol. 2006;117(1):18–24; quiz 25.
192. Fan X, Wang Y. β2 Adrenergic receptor on T lymphocytes and its clinical implications. Prog Nat Sci. 2009;19(1):17–23.
193. Katritch V, Reynolds KA, Cherezov V, Hanson MA, Roth CB, Yeager M, et al. Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes. J Mol Recognit JMR. 2009 Aug;22(4):307–18.
194. Shen A, Chen D, Kaur M, Bartels P, Xu B, Shi Q, et al. β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons. Nelson MT, Boudker O, Xiao R, editors. eLife. 2019 Oct 14;8:e49464.
195. Francis SH, Busch JL, Corbin JD. cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action. Pharmacol Rev. 2010 Sep 1;62(3):525–63.
196. Ozakca I. Antihypertrophic Effects of Nebivolol on Neonatal Cardiomyocyte Hypertrophy Models. J Cardiovasc Pharmacol. 2019 Mar;73(3):155–64.
197. Horinouchi T, Mazaki Y, Terada K, Miwa S. Extracellular Ca2+ promotes nitric oxide production via Ca2+-sensing receptor-Gq/11 protein-endothelial nitric oxide synthase signaling in human vascular endothelial cells. J Pharmacol Sci. 2020 Aug 1;143(4):315–9.
198. Chen C, Du J, Feng W, Song Y, Lu Z, Xu M, et al. β-Adrenergic receptors stimulate interleukin-6 production through Epac-dependent activation of PKCδ/p38 MAPK signalling in neonatal mouse cardiac fibroblasts. Br J Pharmacol. 2012 May;166(2):676–88.
199. Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM, Rajagopal S, et al. Distinct Phosphorylation Sites on the β(2)-Adrenergic Receptor Establish a Barcode That Encodes Differential Functions of β-Arrestin. Sci Signal. 2011;4(185):ra51–ra51.
200. Baillie GS, Houslay MD. Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Curr Opin Cell Biol. 2005;17(2):129–34.
201. Violin JD, Lefkowitz RJ. Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci. 2007;28(8):416–22.
202. Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang KL, et al. Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002 Oct 25;298(5594):834–6.
203. Ahn S, Nelson CD, Garrison TR, Miller WE, Lefkowitz RJ. Desensitization, internalization, and signaling functions of β-arrestins demonstrated by RNA interference. Proc Natl Acad Sci. 2003 Feb 18;100(4):1740–4.
204. O’Hayre M, Eichel K, Avino S, Zhao X, Steffen DJ, Feng X, et al. Genetic evidence that β-arrestins are dispensable for the initiation of β2-adrenergic receptor signaling to ERK. Sci Signal. 2017 Jun 20;10(484).
205. Peaston RT, Weinkove C. Measurement of catecholamines and their metabolites. Ann Clin Biochem. 2004 Jan;41(Pt 1):17–38.
206. Gavriilidou AFM, Hunziker H, Mayer D, Vuckovic Z, Veprintsev DB, Zenobi R. Insights into the Basal Activity and Activation Mechanism of the β1 Adrenergic Receptor Using Native Mass Spectrometry. J Am Soc Mass Spectrom. 2019 Mar;30(3):529–37.
207. Irsfeld M, Spadafore M, M BP. β-Phenylethylamine, a Small Molecule with a Large Impact. WebmedCentral. 2013 30;4(9):4409.
208. Orlovius AK, Guddat S, Parr MK, Kohler M, Gütschow M, Thevis M, et al. Terbutaline sulfoconjugate: characterization and urinary excretion monitored by LC/ESI-MS/MS. Drug Test Anal. 2009;1(11–12):568–75.
209. Olawi N, Kruger M, Grimm D, Infanger M, Wehland M. Nebivolol in the treatment of arterial hypertension. Basic Clin Pharmacol Toxicol. 2019;125(3):189–201.
210. Maack C, Tyroller S, Schnabel P, Cremers B, Dabew E, Südkamp M, et al. Characterization of beta(1)-selectivity, adrenoceptor-G(s)-protein interaction and inverse agonism of nebivolol in human myocardium. Br J Pharmacol. 2001;132(8):1817–26.
211. Ortega VE. Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management. Clin Genet. 2014 Jul;86(1):12–20.
212. Shi L, Liapakis G, Xu R, Guarnieri F, Ballesteros JA, Javitch JA. Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J Biol Chem. 2002 Oct 25;277(43):40989–96.
213. Rasmussen SGF, Choi H-J, Fung JJ, Pardon E, Casarosa P, Chae PS, et al. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature. 2011 Jan 13;469(7329):175–80.
214. Yao XJ, Vélez Ruiz G, Whorton MR, Rasmussen SGF, DeVree BT, Deupi X, et al. The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9501–6.
215. Wisler JW, DeWire SM, Whalen EJ, Violin JD, Drake MT, Ahn S, et al. A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657–62.
216. Small KM, Brown KM, Forbes SL, Liggett SB. Modification of the β2-Adrenergic Receptor to Engineer a Receptor-Effector Complex for Gene Therapy. J Biol Chem. 2001 Aug 24;276(34):31596–601.
217. Liapakis G, Ballesteros JA, Papachristou S, Chan WC, Chen X, Javitch JA. The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the beta 2-adrenergic receptor. J Biol Chem. 2000 Dec 1;275(48):37779–88.
218. Petzold T, Feindt P, Menger MD, Gams E. Beta-adrenoceptor inhibition for induction of acute cardiac failure in pigs. Lab Anim. 1999 Oct;33(4):366–71.
219. Ignarro LJ. Different Pharmacological Properties of Two Enantiomers in a Unique β-Blocker, Nebivolol. Cardiovasc Ther. 2008;26(2):115–34.
220. Broeders MA, Doevendans PA, Bekkers BC, Bronsaer R, van Gorsel E, Heemskerk JW, et al. Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release: endothelial beta(2)-adrenergic receptor-mediated nitric oxide production. Circulation. 2000 Aug 8;102(6):677–84.
221. Shastry BS. SNPs in disease gene mapping, medicinal drug development and evolution. J Hum Genet. 2007 Nov;52(11):871–80.
222. Oostendorp J, Postma DS, Volders H, Jongepier H, Kauffman HF, Boezen HM, et al. Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes. Am J Respir Crit Care Med. 2005;172(3):322–8.
223. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A. 2000;97(19):10483–8.
224. Johnatty SE, Abdellatif M, Shimmin L, Clark RB, Boerwinkle E. β2 adrenergic receptor 5′ haplotypes influence promoter activity. Br J Pharmacol. 2002 Dec;137(8):1213–6.
225. McGraw DW, Forbes SL, Kramer LA, Liggett SB. Polymorphisms of the 5’ leader cistron of the human beta2-adrenergic receptor regulate receptor expression. J Clin Invest. 1998;102(11):1927–32.
226. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem. 1993 Nov 5;268(31):23116–21.
227. Brodde Otto-Erich, Büscher Rainer, Tellkamp Ralph, Radke Joachim, Dhein Stefan, Insel Paul A. Blunted Cardiac Responses to Receptor Activation in Subjects With Thr164Ile β2-Adrenoceptors. Circulation. 2001 Feb 27;103(8):1048–50.
228. Liggett SB. Polymorphisms of the beta2-adrenergic receptor and asthma. Am J Respir Crit Care Med. 1997 Oct;156(4 Pt 2):S156-62.
229. Lipworth BJ, Hall IP, Aziz I, Tan KS, Wheatley A. Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta2-agonist therapy. Clin Sci Lond Engl 1979. 1999;96(3):253–9.
230. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, et al. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med. 2000;162(1):75–80.
231. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet Lond Engl. 2004;364(9444):1505–12.
232. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax. 2000;55(9):762–7.
233. Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, et al. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet Lond Engl. 2009 Nov 21;374(9703):1754–64.
234. Palmer CNA, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Arginine-16 2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax. 2006 Nov 1;61(11):940–4.
235. Ahles A, Rochais F, Frambach T, Bünemann M, Engelhardt S. A polymorphism-specific “memory” mechanism in the β(2)-adrenergic receptor. Sci Signal. 2011 Aug 9;4(185):ra53.
236. Shahane G, Parsania C, Sengupta D, Joshi M. Molecular Insights into the Dynamics of Pharmacogenetically Important N-Terminal Variants of the Human β2-Adrenergic Receptor. PLOS Comput Biol. 2014 Dec 11;10(12):e1004006.
237. Akparova A, Aripova A, Abishev M, Kazhiyakhmetova B, Pirmanova A, Bersimbaev R. An investigation of the association between ADRB2 gene polymorphisms and asthma in Kazakh population. Clin Respir J. 2020;14(6):514–20.
238. Wechsler ME, Castro M, Lehman E, Chinchilli VM, Sutherland ER, Denlinger L, et al. Impact of Race on Asthma Treatment Failures in the Asthma Clinical Research Network. Am J Respir Crit Care Med. 2011 Dec 1;184(11):1247–53.
239. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006 Jan;129(1):15–26.
240. Tsai H-J, Shaikh N, Kho JY, Battle N, Naqvi M, Navarro D, et al. Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics. Hum Genet. 2006 Jun;119(5):547–57.
241. Silvestri M, Oddera S, Scarso L, Pistoia V, Tasso P, Rossi GA. Inhibitory activity of fenoterol on Dermatophagoides-, Parietaria-, tetanus-toxoid-, and Candida albicans-stimulated blood mononuclear cells: differences in beta2-adrenoreceptor stimulation but not in cell apoptosis. J Asthma Off J Assoc Care Asthma. 2000;37(3):281–90.
242. Bartik MM, Brooks WH, Roszman TL. Modulation of T cell proliferation by stimulation of the beta-adrenergic receptor: lack of correlation between inhibition of T cell proliferation and cAMP accumulation. Cell Immunol. 1993;148(2):408–21.
243. Ramer-Quinn DS, Swanson MA, Lee WT, Sanders VM. Cytokine production by naive and primary effector CD4+ T cells exposed to norepinephrine. Brain Behav Immun. 2000;14(4):239–55.
244. Holen E, Elsayed S. Effects of beta2 adrenoceptor agonists on T-cell subpopulations. APMIS Acta Pathol Microbiol Immunol Scand. 1998;106(9):849–57.
245. Edgar VA, Silberman DM, Cremaschi GA, Zieher LM, Genaro AM. Altered lymphocyte catecholamine reactivity in mice subjected to chronic mild stress. Biochem Pharmacol. 2003 Jan 1;65(1):15–23.
246. Wahle M, Neumann RP, Moritz F, Krause A, Buttgereit F, Baerwald CG. Beta2-adrenergic receptors mediate the differential effects of catecholamines on cytokine production of PBMC. J Interferon Cytokine Res Off J Int Soc Interferon Cytokine Res. 2005 Jul;25(7):384–94.
247. Khan MM, Sansoni P, Silverman ED, Engleman EG, Melmon KL. Beta-adrenergic receptors on human suppressor, helper, and cytolytic lymphocytes. Biochem Pharmacol. 1986 Apr 1;35(7):1137–42.
248. Zalli A, Bosch JA, Goodyear O, Riddell N, McGettrick HM, Moss P, et al. Targeting ß2 adrenergic receptors regulate human T cell function directly and indirectly. Brain Behav Immun. 2015 Mar 1;45:211–8.
249. Sanders VM, Baker RA, Ramer-Quinn DS, Kasprowicz DJ, Fuchs BA, Street NE. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol Baltim Md 1950. 1997;158(9):4200–10.
250. McAlees JW, Smith LT, Erbe RS, Jarjoura D, Ponzio NM, Sanders VM. Epigenetic regulation of beta2-adrenergic receptor expression in T(H)1 and T(H)2 cells. Brain Behav Immun. 2011 Mar;25(3):408–15.
251. Agarwal SK, Marshall GD. Beta-adrenergic modulation of human type-1/type-2 cytokine balance. J Allergy Clin Immunol. 2000 Jan;105(1 Pt 1):91–8.
252. Huang HW, Tang JL, Han XH, Peng YP, Qiu YH. Lymphocyte-derived catecholamines induce a shift of Th1/Th2 balance toward Th2 polarization. Neuroimmunomodulation. 2013;20(1):1–8.
253. Salicrú AN, Sams CF, Marshall GD. Cooperative effects of corticosteroids and catecholamines upon immune deviation of the type-1/type-2 cytokine balance in favor of type-2 expression in human peripheral blood mononuclear cells. Brain Behav Immun. 2007 Oct 1;21(7):913–20.
254. Kim BJ, Jones HP. Epinephrine-primed murine bone marrow-derived dendritic cells facilitate production of IL-17A and IL-4 but not IFN-gamma by CD4+ T cells. Brain Behav Immun. 2010 Oct;24(7):1126–36.
255. Manni M, Granstein RD, Maestroni G. beta2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response. Cytokine. 2011 Sep;55(3):380–6.
256. Case AJ, Roessner CT, Tian J, Zimmerman MC. Mitochondrial Superoxide Signaling Contributes to Norepinephrine-Mediated T-Lymphocyte Cytokine Profiles. PloS One. 2016 Oct 11;11(10):e0164609.
257. Liu Y, Rui XX, Shi H, Qiu YH, Peng YP. Norepinephrine Inhibits Th17 Cells via beta2-Adrenergic Receptor (beta2-AR) Signaling in a Mouse Model of Rheumatoid Arthritis. Med Sci Monit Int Med J Exp Clin Res. 2018;24:1196–204.
258. Wang JH, Meijers R, Xiong Y, Liu JH, Sakihama T, Zhang R, et al. Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10799–804.
259. Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev. 2008;8(5):337–48.
260. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol. 2002;3(6):549–57.
261. Romagnani S, Maggi E, Liotta F, Cosmi L, Annunziato F. Properties and origin of human Th17 cells. Mol Immunol. 2009 Nov;47(1):3–7.
262. Becattini S, Latorre D, Mele F, Foglierini M, Gregorio CD, Cassotta A, et al. T cell immunity. Functional heterogeneity of human memory CD4(+) T cell clones primed by pathogens or vaccines. Science. 2015 Jan 23;347(6220):400–6.
263. Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, et al. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature. 2012 Apr 26;484(7395):514–8.
264. Sanders VM. The beta2-adrenergic receptor on T and B lymphocytes: Do we understand it yet? Brain Behav Immun. 2012;26(2):195–200.
265. Swanson MA, Lee WT, Sanders VM. IFN-gamma production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. J Immunol Baltim Md 1950. 2001;166(1):232–40.
266. Borger P, Hoekstra Y, Esselink MT, Postma DS, Zaagsma J, Vellenga E, et al. Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Am J Respir Cell Mol Biol. 1998 Sep;19(3):400–7.
267. Torres KC, Antonelli LR, Souza AL, Teixeira MM, Dutra WO, Gollob KJ. Norepinephrine, dopamine and dexamethasone modulate discrete leukocyte subpopulations and cytokine profiles from human PBMC. J Neuroimmunol. 2005;166(1–2):144–57.
268. Ramer-Quinn DS, Baker RA, Sanders VM. Activated T helper 1 and T helper 2 cells differentially express the beta-2-adrenergic receptor: a mechanism for selective modulation of T helper 1 cell cytokine production. J Immunol Baltim Md 1950. 1997;159(10):4857–67.
269. Kalinichenko VV, Mokyr MB, Graf LH Jr, Cohen RL, Chambers DA. Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression. J Immunol Baltim Md 1950. 1999;163(5):2492–9.
270. Kohm AP, Sanders VM. Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev. 2001;53(4):487–525.
271. Guereschi MG, Araujo LP, Maricato JT, Takenaka MC, Nascimento VM, Vivanco BC, et al. Beta2-adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner. Eur J Immunol. 2013 Apr;43(4):1001–12.
272. Kin NW, Sanders VM. It takes nerve to tell T and B cells what to do. J Leukoc Biol. 2006;79(6):1093–104.
273. Touil T, Fitzgerald D, Zhang GX, Rostami AM, Gran B. Pathophysiology of interleukin-23 in experimental autoimmune encephalomyelitis. Drug News Perspect. 2006;19(2):77–83.
274. Tabatabaei Shafiei M, Carvajal Gonczi C M, Rahman MS, East A, François J, Darlington PJ. Detecting Glycogen in Peripheral Blood Mononuclear Cells with Periodic Acid Schiff Staining. J Vis Exp JoVE. 2014;(94):52199.
275. Quah BJ, Parish CR. The use of carboxyfluorescein diacetate succinimidyl ester (CFSE) to monitor lymphocyte proliferation. J Vis Exp JoVE. 2010 Oct 12;(44). pii: 2259. doi(44):10.3791/2259.
276. Maestroni GJ. Short exposure of maturing, bone marrow-derived dendritic cells to norepinephrine: impact on kinetics of cytokine production and Th development. J Neuroimmunol. 2002;129(1–2):106–14.
277. Ortega VE, Hawkins GA, Moore WC, Hastie AT, Ampleford EJ, Busse WW, et al. Effect of RareGenetic Variants in the β2 Adrenergic Receptor Geneon the Risk for Exacerbations and Symptom Control During Long-Acting Beta Agonist Treatment in a Multi-Ethnic Asthma Population. Lancet Respir Med. 2014;2(3):204–13.
278. Nordlind K, Sundstrom E. Different modulating effects of the monoamines adrenaline, noradrenaline, and serotonin on the DNA synthesis response of human peripheral blood T lymphocytes activated by mercuric chloride and nickel sulfate. Int Arch Allergy Appl Immunol. 1988;87(3):317–20.
279. Carlson SL, Brooks WH, Roszman TL. Neurotransmitter-lymphocyte interactions: dual receptor modulation of lymphocyte proliferation and cAMP production. J Neuroimmunol. 1989;24(1–2):155–62.
280. Felsner P, Hofer D, Rinner I, Mangge H, Gruber M, Korsatko W, et al. Continuous in vivo treatment with catecholamines suppresses in vitro reactivity of rat peripheral blood T-lymphocytes via alpha-mediated mechanisms. J Neuroimmunol. 1992;37(1–2):47–57.
281. Elliott L, Brooks W, Roszman T. Inhibition of anti-CD3 monoclonal antibody-induced T-cell proliferation by dexamethasone, isoproterenol, or prostaglandin E2 either alone or in combination. Cell Mol Neurobiol. 1992;12(5):411–27.
282. Heilig M, Irwin M, Grewal I, Sercarz E. Sympathetic regulation of T-helper cell function. Brain Behav Immun. 1993;7(2):154–63.
283. Borger P, Kauffman HF, Vijgen JL, Postma DS, Vellenga E. Activation of the cAMP-dependent signaling pathway downregulates the expression of interleukin-3 and granulocyte-macrophage colony-stimulating factor in activated human T lymphocytes. Exp Hematol. 1996;24(2):108–15.
284. Bartik MM, Bauman GP, Brooks WH, Roszman TL. Costimulatory signals modulate the antiproliferative effects of agents that elevate cAMP in T cells. Cell Immunol. 1994;158(1):116–30.
285. Bjorgo E, Tasken K. Role of cAMP phosphodiesterase 4 in regulation of T-cell function. Crit Rev Immunol. 2006;26(5):443–51.
286. Saeki K, Fukuyama S, Ayada T, Nakaya M, Aki D, Takaesu G, et al. A major lipid raft protein raftlin modulates T cell receptor signaling and enhances th17-mediated autoimmune responses. J Immunol Baltim Md 1950. 2009 May 15;182(10):5929–37.
287. Li X, Murray F, Koide N, Goldstone J, Dann SM, Chen J, et al. Divergent requirement for Galphas and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets. J Clin Invest. 2012 Mar;122(3):963–73.
288. Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009;66(3):390–402.
289. Bystrom J, Taher TE, Muhyaddin MS, Clanchy FI, Mangat P, Jawad AS, et al. Harnessing the Therapeutic Potential of Th17 Cells. Mediators Inflamm. 2015;2015(Journal Article):205156.
290. Huang HW, Fang XX, Wang XQ, Peng YP, Qiu YH. Regulation of differentiation and function of helper T cells by lymphocyte-derived catecholamines via alpha(1)- and beta(2)-adrenoceptors. Neuroimmunomodulation. 2015;22(3):138–51.
291. Laukova M, Vargovic P, Vlcek M, Lejavova K, Hudecova S, Krizanova O, et al. Catecholamine production is differently regulated in splenic T- and B-cells following stress exposure. Immunobiology. 2013 May;218(5):780–9.
292. Cosentino M, Bombelli R, Ferrari M, Marino F, Rasini E, Maestroni GJ, et al. HPLC-ED measurement of endogenous catecholamines in human immune cells and hematopoietic cell lines. Life Sci. 2000;68(3):283–95.
293. Liu Y, Huang Y, Wang XQ, Peng YP, Qiu YH. Effect of tyrosine hydroxylase gene silencing in CD4+ T lymphocytes on differentiation and function of helper T cells. Neuro Endocrinol Lett. 2012;33(6):643–50.
294. Cosentino M, Fietta AM, Ferrari M, Rasini E, Bombelli R, Carcano E, et al. Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood. 2007;109(2):632–42.
295. Musso NR, Brenci S, Setti M, Indiveri F, Lotti G. Catecholamine content and in vitro catecholamine synthesis in peripheral human lymphocytes. J Clin Endocrinol Metab. 1996 Oct;81(10):3553–7.
296. Liu Z, Han B, Li P, Wang Z, Fan Q. Activation of alpha7nAChR by nicotine reduced the Th17 response in CD4(+)T lymphocytes. Immunol Invest. 2014;43(7):667–74.
297. Lorton D, Bellinger DL. Molecular mechanisms underlying beta-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci. 2015 Mar 11;16(3):5635–65.
298. Xiang L, Rehm KE, Sunesara I, Griswold M, Jr GDM. Gene polymorphisms of stress hormone and cytokine receptors associate with immunomodulatory profile and psychological measurement. J Psychosom Res. 2015 May;78(5):438–44.
299. Shao T-Y, Ang WXG, Jiang TT, Huang FS, Andersen H, Kinder JM, et al. Commensal Candida albicans Positively Calibrates Systemic Th17 Immunological Responses. Cell Host Microbe. 2019 Mar 13;25(3):404-417.e6.
300. Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13(6):668–77.
301. Prajeeth CK, Kronisch J, Khorooshi R, Knier B, Toft-Hansen H, Gudi V, et al. Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties. J Neuroinflammation. 2017 Oct 16;14.
302. Yasuda K, Takeuchi Y, Hirota K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol. 2019 May 1;41(3):283–97.
303. Carvajal Gonczi CM, Tabatabaei Shafiei M, East A, Martire E, Maurice-Ventouris MHI, Darlington PJ. Reciprocal modulation of helper Th1 and Th17 cells by the β2-adrenergic receptor agonist drug terbutaline. FEBS J. 2017 Sep;284(18):3018–28.
304. Kahsai A W, Xiao Kunhong, Rajagopal Sudarshan, Ahn Seungkirl, Shukla A K, Sun Jinpeng, et al. Multiple ligand-specific conformations of the β2-adrenergic receptor. 2011;7(10).
305. Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68(Journal Article):821–61.
306. Hsueh YP, Liang HE, Ng SY, Lai MZ. CD28-costimulation activates cyclic AMP-responsive element-binding protein in T lymphocytes. J Immunol Baltim Md 1950. 1997;158(1):85–93.
307. Grady GC, Mason SM, Stephen J, Zuniga-Pflucker JC, Michie AM. Cyclic adenosine 5’-monophosphate response element binding protein plays a central role in mediating proliferation and differentiation downstream of the pre-TCR complex in developing thymocytes. J Immunol Baltim Md 1950. 2004;173(3):1802–10.
308. Pasquinelli V, Townsend JC, Jurado JO, Alvarez IB, Quiroga MF, Barnes PF, et al. IFN-γ Production during Active Tuberculosis Is Regulated by Mechanisms That Involve IL-17, SLAM, and CREB. J Infect Dis. 2009;199(5):661–5.
309. Tsai HC, Velichko S, Lee S, Wu R. Cholera toxin enhances interleukin-17A production in both CD4(+) and CD8(+) cells via a cAMP/protein kinase A-mediated interleukin-17A promoter activation. Immunology. 2018;(Journal Article).
310. Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Cell Biol. 2001 Aug;2(8):599–609.
311. Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989;59(4):675–80.
312. Dostmann WR. (RP)-cAMPS inhibits the cAMP-dependent protein kinase by blocking the cAMP-induced conformational transition. FEBS Lett. 1995;375(3):231–4.
313. Lynch MJ, Baillie GS, Mohamed A, Li X, Maisonneuve C, Klussmann E, et al. RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. J Biol Chem. 2005;280(39):33178–89.
314. Baroja ML, Cieslinski LB, Torphy TJ, Wange RL, Madrenas J. Specific CD3 epsilon association of a phosphodiesterase 4B isoform determines its selective tyrosine phosphorylation after CD3 ligation. J Immunol Baltim Md 1950. 1999;162(4):2016–23.
315. Reiter E, Ahn S, Shukla AK, Lefkowitz RJ. Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol. 2012;52:179–97.
316. Sanders VM, Straub RH. Norepinephrine, the beta-adrenergic receptor, and immunity. Brain Behav Immun. 2002;16(4):290–332.
317. Chung Y, Pasquinelli V, Jurado JO, Wang X, Yi N, Barnes PF, et al. Elevated Cyclic AMP Inhibits Mycobacterium tuberculosis-Stimulated T-cell IFN-γ Secretion Through Type I Protein Kinase A. J Infect Dis. 2018 May 5;217(11):1821–31.
318. Zhang F, Wang DZ, Boothby M, Penix L, Flavell RA, Aune TM. Regulation of the activity of IFN-gamma promoter elements during Th cell differentiation. J Immunol Baltim Md 1950. 1998 Dec 1;161(11):6105–12.
319. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, et al. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med. 2009 Mar 16;206(3):535–48.
320. Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, et al. Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat Med. 2009 Jun;15(6):633–40.
321. Gonzalez-Garcia C, Bravo B, Ballester A, Gomez-Perez R, Eguiluz C, Redondo M, et al. Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis. Br J Pharmacol. 2013;170(3):602–13.
322. Jimenez JL, Punzón C, Navarro J, Muñoz-Fernández MA, Fresno M. Phosphodiesterase 4 Inhibitors Prevent Cytokine Secretion by T Lymphocytes by Inhibiting Nuclear Factor-κB and Nuclear Factor of Activated T Cells Activation. J Pharmacol Exp Ther. 2001 Nov 1;299(2):753–9.
323. Beltejar MG, Lau HT, Golkowski MG, Ong SE, Beavo JA. Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells. Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6240–9.
324. Lochner A, Moolman JA. The many faces of H89: a review. Cardiovasc Drug Rev. 2006;24(3–4):261–74.
325. Stockinger B, Omenetti S. The dichotomous nature of T helper 17 cells. Nat Rev Immunol. 2017 Sep;17(9):535–44.
326. Lu Y-J, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q, et al. Interleukin-17A Mediates Acquired Immunity to Pneumococcal Colonization. PLOS Pathog. 2008 Sep 19;4(9):e1000159.
327. Jovanovic DV, Battista JAD, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, et al. IL-17 Stimulates the Production and Expression of Proinflammatory Cytokines, IL-β and TNF-α, by Human Macrophages. J Immunol. 1998 Apr 1;160(7):3513–21.
328. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 Production in Central Nervous System-Infiltrating T Cells and Glial Cells Is Associated with Active Disease in Multiple Sclerosis. Am J Pathol. 2008 Jan;172(1):146–55.
329. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain J Neurol. 2009 Dec;132(Pt 12):3329–41.
330. Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol. 2009 May;65(5):499–509.
331. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999 May 1;103(9):1345–52.
332. Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS, et al. cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci. 1987 Jan 1;84(1):46–50.
333. Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, et al. Diverse Evolutionary Histories for β-adrenoreceptor Genes in Humans. Am J Hum Genet. 2009;85(1):64–75.
334. Hall IP. Beta 2 adrenoceptor polymorphisms: are they clinically important? Thorax. 1996;51(4):351–3.
335. Theron AJ, Steel HC, Tintinger GR, Feldman C, Anderson R. Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting? Drug Des Devel Ther. 2013;7:1387–98.
336. Carvajal Gonczi CM, Tabatabaei Shafiei M, East A, Martire E, Maurice‐Ventouris MHI, Darlington PJ. Reciprocal modulation of helper Th1 and Th17 cells by the β2‐adrenergic receptor agonist drug terbutaline. FEBS J. 2017;284(18):3018–28.
337. Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol. 2005;144(3):317–22.
338. Loftus GR, Masson ME. Using confidence intervals in within-subject designs. Psychon Bull Rev. 1994 Dec;1(4):476–90.
339. Robert M, Miossec P. IL-17 in Rheumatoid Arthritis and Precision Medicine: From Synovitis Expression to Circulating Bioactive Levels. Front Med. 2019 Jan 14;5.
340. Bacher P, Hohnstein T, Beerbaum E, Röcker M, Blango MG, Kaufmann S, et al. Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans. Cell. 2019 Mar 7;176(6):1340-1355.e15.
341. Olawi N, Krüger M, Grimm D, Infanger M, Wehland M. Nebivolol in the treatment of arterial hypertension. Basic Clin Pharmacol Toxicol. 2019 Sep;125(3):189–201.
342. Obermajer N, Wong JL, Edwards RP, Chen K, Scott M, Khader S, et al. Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. J Exp Med. 2013 Jul 1;210(7):1433–45.
343. Bhosale S, Nikte SV, Sengupta D, Joshi M. Differential Dynamics Underlying the Gln27Glu Population Variant of the β2-Adrenergic Receptor. J Membr Biol. 2019 Oct;252(4–5):499–507.
344. Abraham RT, Weiss A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat Rev Immunol. 2004 Apr;4(4):301–8.
345. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33(32):9414–9.
346. Kaszuba K, Róg T, Bryl K, Vattulainen I, Karttunen M. Molecular dynamics simulations reveal fundamental role of water as factor determining affinity of binding of β-blocker nebivolol to β2-adrenergic receptor. J Phys Chem B. 2010;114(25):8374–86.
347. Liggett SB. Update on current concepts of the molecular basis of beta2-adrenergic receptor signaling. J Allergy Clin Immunol. 2002;110(6 Suppl):S223-7.
348. Cameron RB, Peterson YK, Beeson CC, Schnellmann RG. Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol. Sci Rep. 2017 Sep 5;7(1):10578.
349. Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, Ameredes BT, et al. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet Lond Engl. 2009;374(9703):1754–64.
350. Xu D, Wu Y, Gao C, Qin Y, Zhao X, Liang Z, et al. Characteristics of and reference ranges for peripheral blood lymphocytes and CD4+ T cell subsets in healthy adults in Shanxi Province, North China. J Int Med Res. 2020 Jul 10;48(7).
351. Żbikowska-Gotz M, Pałgan K, Gawrońska-Ukleja E, Kuźmiński A, Przybyszewski M, Socha E, et al. Expression of IL-17A concentration and effector functions of peripheral blood neutrophils in food allergy hypersensitivity patients. Int J Immunopathol Pharmacol. 2016 Mar;29(1):90–8.
352. Tasken K, Stokka AJ. The molecular machinery for cAMP-dependent immunomodulation in T-cells. Biochem Soc Trans. 2006;34(Pt 4):476–9.
353. Cornez I, Tasken K. Spatiotemporal control of cyclic AMP immunomodulation through the PKA-Csk inhibitory pathway is achieved by anchoring to an Ezrin-EBP50-PAG scaffold in effector T cells. FEBS Lett. 2010;584(12):2681–8.
354. Krause DS, Deutsch C. Cyclic AMP directly inhibits IL-2 receptor expression in human T cells: expression of both p55 and p75 subunits is affected. J Immunol Baltim Md 1950. 1991;146(7):2285–96.
355. Lee J, Aoki T, Thumkeo D, Siriwach R, Yao C, Narumiya S. T cell–intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell–driven inflammation. J Allergy Clin Immunol. 2019 Feb;143(2):631–43.
356. Liu W, Li H, Zhang X, Wen D, Yu F, Yang S, et al. Prostaglandin I2-IP signalling regulates human Th17 and Treg cell differentiation. Prostaglandins Leukot Essent Fatty Acids. 2013;89(5):335–44.
357. Suárez A, Mozo L, Gutiérrez C. Generation of CD4+CD45RA+ Effector T Cells by Stimulation in the Presence of Cyclic Adenosine 5′-Monophosphate- Elevating Agents. J Immunol. 2002 Aug 1;169(3):1159–67.
358. Orbán C, Vásárhelyi Z, Bajnok A, Sava F, Toldi G. Effects of caffeine and phosphodiesterase inhibitors on activation of neonatal T lymphocytes. Immunobiology. 2018 Nov;223(11):627–33.
359. Essayan DM, Huang SK, Kagey-Sobotka A, Lichtenstein LM. Effects of nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors on antigen-induced cytokine gene expression in peripheral blood mononuclear cells. Am J Respir Cell Mol Biol. 1995;13(6):692–702.
360. Bielekova B, Lincoln A, McFarland H, Martin R. Therapeutic potential of phosphodiesterase-4 and -3 inhibitors in Th1-mediated autoimmune diseases. J Immunol. 2000;164(2):1117–24.
361. Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E2 and T cells: friends or foes? Immunol Cell Biol. 2012 Jul;90(6):579–86.
362. Napolitani G, Acosta-Rodriguez EV, Lanzavecchia A, Sallusto F. Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+ T cells. Eur J Immunol. 2009 May;39(5):1301–12.
363. Wu Q, Wang Q, Mao G, Dowling CA, Lundy SK, Mao-Draayer Y. Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients. J Immunol. 2017 Apr 15;198(8):3069–80.
364. Brod SA. In MS: Immunosuppression is passé. Mult Scler Relat Disord. 2020 May 1;40.
365. Bodor J, Bodorova J, Gress RE. Suppression of T cell function: a potential role for transcriptional repressor ICER. J Leukoc Biol. 2000;67(6):774–9.
366. Bodor J, Habener JF. Role of transcriptional repressor ICER in cyclic AMP-mediated attenuation of cytokine gene expression in human thymocytes. J Biol Chem. 1998 Apr 17;273(16):9544–51.
367. Araujo LP, Maricato JT, Guereschi MG, Takenaka MC, Nascimento VM, de Melo FM, et al. The Sympathetic Nervous System Mitigates CNS Autoimmunity via β2-Adrenergic Receptor Signaling in Immune Cells. Cell Rep. 2019 Sep 17;28(12):3120-3130.e5.
368. Yoshida N, Comte D, Mizui M, Otomo K, Rosetti F, Mayadas TN, et al. ICER is requisite for Th17 differentiation. Nat Commun. 2016 Sep 29;7(1):12993.
369. Hofmann SR, Mäbert K, Kapplusch F, Russ S, Northey S, Beresford MW, et al. cAMP Response Element Modulator α Induces Dual Specificity Protein Phosphatase 4 to Promote Effector T Cells in Juvenile-Onset Lupus. J Immunol Baltim Md 1950. 2019 Dec 1;203(11):2807–16.
370. Zhao P, Song Z, Wang Y, Cai H, Du X, Li C, et al. The endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase G pathway activates primordial follicles. Aging. 2020 Dec 3;12.
371. Birder LA, Nealen ML, Kiss S, Groat WC de, Caterina MJ, Wang E, et al. β-Adrenoceptor Agonists Stimulate Endothelial Nitric Oxide Synthase in Rat Urinary Bladder Urothelial Cells. J Neurosci. 2002 Sep 15;22(18):8063–70.
372. Xue Q, Yan Y, Zhang R, Xiong H. Regulation of iNOS on Immune Cells and Its Role in Diseases. Int J Mol Sci. 2018 Nov 29;19(12).
373. Niedbala W, Alves-Filho JC, Fukada SY, Vieira SM, Mitani A, Sonego F, et al. Regulation of type 17 helper T-cell function by nitric oxide during inflammation. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9220–5.
374. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF, Boushey HA, Deykin A, et al. β-Adrenergic Receptor Polymorphisms and Response to Salmeterol. Am J Respir Crit Care Med. 2006 Mar;173(5):519–26.
375. Kotla S, Singh NK, Heckle MR, Tigyi GJ, Rao GN. The Transcription Factor CREB Enhances Interleukin-17A Production and Inflammation in a Mouse Model of Atherosclerosis. Sci Signal. 2013 Sep 17;6(293):ra83–ra83.
376. Bagshaw ORM, De Lange M, Renda S, Valente AJF, Stuart JA. Hypoxio: a simple solution to preventing pericellular hypoxia in cell monolayers growing at physiological oxygen levels. Cytotechnology. 2019 Aug;71(4):873–9.
377. Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015 May 21;161(5):1202–14.
378. Gagnon DD, Gagnon SS, Rintamaki H, Tormakangas T, Puukka K, Herzig KH, et al. The effects of cold exposure on leukocytes, hormones and cytokines during acute exercise in humans. PloS One. 2014 Oct 22;9(10):e110774.
379. Zhang Y, Jing Y, Qiao J, Luan B, Wang X, Wang L, et al. Activation of the mTOR signaling pathway is required for asthma onset. Sci Rep. 2017;7(1):4532–4532.
380. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020 Dec;588(7837):315–20.
381. Panina-Bordignon P, Mazzeo D, Lucia PD, D’Ambrosio D, Lang R, Fabbri L, et al. Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12. J Clin Invest. 1997;100(6):1513–9.
382. Makhlouf K, Comabella M, Imitola J, Weiner HL, Khoury SJ. Oral salbutamol decreases IL-12 in patients with secondary progressive multiple sclerosis. J Neuroimmunol. 2001;117(1–2):156–65.
383. Heesen C, Gold SM, Sondermann J, Tessmer W, Schulz K-H. Oral terbutaline differentially affects cytokine (IL-10, IL-12, TNF, IFNg) release in multiple sclerosis patients and controls. J Neuroimmunol. 2002 Nov;132(1–2):189–95.
384. Newcomb DC, Peebles RS. Th17-mediated inflammation in asthma. Curr Opin Immunol. 2013;25(6):10.1016/j.coi.2013.08.002.
385. Borish L, Culp JA. Asthma: a syndrome composed of heterogeneous diseases. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2008 Jul;101(1):1–8; quiz 8–11, 50.
386. McKinley L, Alcorn JF, Peterson A, DuPont RB, Kapadia S, Logar A, et al. T(H)17 Cells Mediate Steroid-Resistant Airway Inflammation and Airway Hyperresponsiveness in Mice. J Immunol Baltim Md 1950. 2008;181(6):4089–97.
387. Alcorn JF, Crowe CR, Kolls JK. TH17 cells in asthma and COPD. Annu Rev Physiol. 2010;72:495–516.
388. Keranen T, Hommo T, Moilanen E, Korhonen R. beta2-receptor agonists salbutamol and terbutaline attenuated cytokine production by suppressing ERK pathway through cAMP in macrophages. Cytokine. 2017;94(Journal Article):1–7.
389. Cohen S, Tyrrell DA, Smith AP. Psychological stress and susceptibility to the common cold. N Engl J Med. 1991;325(9):606–12.
390. Chmura J, Chmura P, Konefał M, Batra A, Mroczek D, Kosowski M, et al. The Effects of a Marathon Effort on Psychomotor Performance and Catecholamine Concentration in Runners over 50 Years of Age. Appl Sci. 2020 Jan;10(6):2067.
391. Rehm K, Sunesara I, Marshall GD. Increased Circulating Anti-inflammatory Cells in Marathon-trained Runners. Int J Sports Med. 2015 Oct;36(10):832–6.
392. Xiang L, Ben KSD, Rehm KE, Gailen D. Marshall J. Effects of Acute Stress-Induced Immunomodulation on Th1/Th2 Cytokine and Catecholamine Receptor Expression in Human Peripheral Blood Cells. Neuropsychobiology. 2012;65(1):12–9.
393. Swanson MA, Lee WT, Sanders VM. IFN-γ Production by Th1 Cells Generated from Naive CD4 + T Cells Exposed to Norepinephrine. J Immunol. 2001 Jan 1;166(1):232–40.
394. Sanders VM. The role of adrenoceptor-mediated signals in the modulation of lymphocyte function. Adv Neuroimmunol. 1995;5(3):283–98.
395. Elenkov IJ, Papanicolaou DA, Wilder RL, Chrousos GP. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Am Physicians. 1996;108(5):374–81.
396. Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci. 2002;966(Journal Article):290–303.
397. GraphPad Prism 7 Statistics Guide - How the Holm-Sidak method works [Internet]. [cited 2021 Jan 5]. Available from: https://www.graphpad.com/guides/prism/7/statistics/stat_how_the_holm_method_woks.htm
398. Guo W, Romano J. A generalized Sidak-Holm procedure and control of generalized error rates under independence. Stat Appl Genet Mol Biol. 2007;6:Article3.
399. Langsrud Ø. ANOVA for unbalanced data: Use Type II instead of Type III sums of squares. Stat Comput. 2003 Apr 1;13(2):163–7.
400. Ledbetter JA, Parsons M, Martin PJ, Hansen JA, Rabinovitch PS, June CH. Antibody binding to CD5 (Tp67) and Tp44 T cell surface molecules: effects on cyclic nucleotides, cytoplasmic free calcium, and cAMP-mediated suppression. J Immunol Baltim Md 1950. 1986;137(10):3299–305.
401. N. Smith IB S Lai Wing Sun, T Babiuk-Henry, A Elhalwi, J Francois, A Ghassemi, M Tabatabaei Shafiei, PJDarlington. The sympathetic catecholamine norepinephrine increases Th17 responses in a β2-adrenergic receptor-dependent manner. [conference proceedings]. In: J Neuroimmunol. 2012. p. 56–7.
Repository Staff Only: item control page