HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, H. Articles by Hoskin, D. W. Search for Related Content PubMed PubMed Citation Articles by Zhang, H. Articles by Hoskin, D. W.

Adenosine Acts through A₂ Receptors to Inhibit IL-2-Induced Tyrosine Phosphorylation of STAT5 in T Lymphocytes: Role of Cyclic Adenosine 3',5'-Monophosphate and Phosphatases¹

Hong Zhang^*, David M. Conrad^*, Jared J. Butler^*, Chuanli Zhao^*, Jonathan Blay and David W. Hoskin^2,*,

Departments of ^* Microbiology and Immunology, Pharmacology, and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada

Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A₁, A_2a, A_2b, A₃) on responsive cells such as T lymphocytes. IL-2 is a major T cell growth and survival factor that is responsible for inducing Jak1, Jak3, and STAT5 phosphorylation, as well as causing STAT5 to translocate to the nucleus and bind regulatory elements in the genome. In this study, we show that adenosine suppressed IL-2-dependent proliferation of CTLL-2 T cells by inhibiting STAT5a/b tyrosine phosphorylation that is associated with IL-2R signaling without affecting IL-2-induced phosphorylation of Jak1 or Jak3. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reversed by the protein tyrosine phosphatase inhibitors sodium orthovanadate and bpV(phen). Adenosine dramatically increased Src homology region 2 domain-containing phosphatase-2 (SHP-2) tyrosine phosphorylation and its association with STAT5 in IL-2-stimulated CTLL-2 T cells, implicating SHP-2 in adenosine-induced STAT5a/b dephosphorylation. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reproduced by A₂ receptor agonists and was blocked by selective A_2a and A_2b receptor antagonists, indicating that adenosine was mediating its effect through A₂ receptors. Inhibition of STAT5a/b phosphorylation was reproduced with cell-permeable 8-bromo-cAMP or forskolin-induced activation of adenylyl cyclase, and blocked by the cAMP/protein kinase A inhibitor Rp-cAMP. Forskolin and 8-bromo-cAMP also induced SHP-2 tyrosine phosphorylation. Collectively, these findings suggest that adenosine acts through A₂ receptors and associated cAMP/protein kinase A-dependent signaling pathways to activate SHP-2 and cause STAT5 dephosphorylation that results in reduced IL-2R signaling in T cells.

This article has been cited by other articles:

				F. Jeffe, K. A. Stegmann, F. Broelsch, M. P. Manns, M. Cornberg, and H. Wedemeyer Adenosine and IFN-{alpha} synergistically increase IFN-{gamma} production of human NK cells J. Leukoc. Biol., March 1, 2009; 85(3): 452 - 461. [Abstract] [Full Text] [PDF]

				B. Csoka, L. Himer, Z. Selmeczy, E. S. Vizi, P. Pacher, C. Ledent, E. A. Deitch, Z. Spolarics, Z. H. Nemeth, and G. Hasko Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function FASEB J, October 1, 2008; 22(10): 3491 - 3499. [Abstract] [Full Text] [PDF]

				B. Csoka, Z. H. Nemeth, L. Virag, P. Gergely, S. J. Leibovich, P. Pacher, C.-X. Sun, M. R. Blackburn, E. S. Vizi, E. A. Deitch, et al. A2A adenosine receptors and C/EBP{beta} are crucially required for IL-10 production by macrophages exposed to Escherichia coli Blood, October 1, 2007; 110(7): 2685 - 2695. [Abstract] [Full Text] [PDF]

				E. Y. Tan, C. L. Richard, H. Zhang, D. W. Hoskin, and J. Blay Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway Am J Physiol Cell Physiol, September 1, 2006; 291(3): C433 - C444. [Abstract] [Full Text] [PDF]

				J. Hoogendam, E. Parlevliet, R. Miclea, C. W. G. M. Lowik, J. M. Wit, and M. Karperien Novel Early Target Genes of Parathyroid Hormone-Related Peptide in Chondrocytes Endocrinology, June 1, 2006; 147(6): 3141 - 3152. [Abstract] [Full Text] [PDF]

				Z. H. Nemeth, B. Csoka, J. Wilmanski, D. Xu, Q. Lu, C. Ledent, E. A. Deitch, P. Pacher, Z. Spolarics, and G. Hasko Adenosine A2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis J. Immunol., May 1, 2006; 176(9): 5616 - 5626. [Abstract] [Full Text] [PDF]

				C. Bulin, U. Albrecht, J.G. Bode, A.-A. Weber, K. Schror, B. Levkau, and J.W. Fischer Differential Effects of Vasodilatory Prostaglandins on Focal Adhesions, Cytoskeletal Architecture, and Migration in Human Aortic Smooth Muscle Cells Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 84 - 89. [Abstract] [Full Text] [PDF]