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 phosphatases

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

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

102 Citas (Scopus)

Resumen

Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A1, A2, A2b, 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 A2a and A2b 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.

Idioma originalEnglish
Páginas (desde-hasta)932-944
Número de páginas13
PublicaciónJournal of Immunology
Volumen173
N.º2
DOI
EstadoPublished - jul. 15 2004

ASJC Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Huella

Profundice en los temas de investigación de '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 phosphatases'. En conjunto forman una huella única.

Citar esto