Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E-2 and other cyclic adenosine monophosphate-elevating agents: Impact on interleukin-2 receptor signaling pathway

The Janus kinase, JAK3 plays an important role in interleukin-a (IL-a)-depe ndent signal transduction and proliferation of T lymphocytes. Our findings show that prostaglandin E-2 (PGE(2)) can inhibit upregulation of JAK3 prote in in naive T cells and can downregulate its expression in primed cells. Re duction in JAK3 was selective because expression of other tyrosine kinases (JAK1, p56(lck), and p59(fyn)) and signal transducer and activator of trans cription (STAT)5, which are linked to IL-2 receptor (IL-2R) signaling pathw ay, were not affected. Inhibition of JAK3 may be controlled by intracellula r cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct acti vator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeabl e analogue of cAMP suppressed JAK3 expression. Moreover, 8-isobutyl-1-methy l-xanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE( 2)-induced suppression of JAK3, In naive T cells, but not primed T cells, P GE(2) and other cAMP elevating agents also caused a modest reduction in sur face expression of the common gamma chain (gamma c) that associates with JA K3, The absence of JAK3, but not IL-SR in T cells correlated with impaired IL-2-dependent signal transduction and proliferation. The alteration in IL- 2 signaling included decreased tyrosine phosphorylation and DNA binding act ivity of STAT5 and poor induction of the c-Myc and c-Jun pathways, In contr ast, IL-2-dependent induction of Bcl-2 was unaffected, These findings sugge st that suppression of JAK3 levels may represent one mechanism by which PGE (2) and other cAMP elevating agents can inhibit T-cell proliferation. (C) 1 999 by The American Society of Hematology.