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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2308-2318
Downregulation of JAK3 Protein Levels in T Lymphocytes by Prostaglandin
E2 and Other Cyclic Adenosine Monophosphate-Elevating
Agents: Impact on Interleukin-2 Receptor Signaling Pathway
Vladimir Kolenko,
Patricia Rayman,
Biswajit Roy,
Martha K. Cathcart,
John O'Shea,
Raymond Tubbs,
Lisa Rybicki,
Ronald Bukowski, and
James Finke
From the Departments of Immunology, Cell Biology, Clinical Pathology,
Biostatistics and Epidemiology, and Hematology-Oncology, Cleveland
Clinic Foundation, Cleveland, OH; and Lymphocyte Cell Biology Section,
Arthritis and Rheumatism Branch, National Institute of Arthritis and
Musculoskeletal and Skin Diseases, Bethesda MD.
The Janus kinase, JAK3 plays an important role in interleukin-2
(IL-2)-dependent signal transduction and proliferation of T
lymphocytes. Our findings show that prostaglandin E2
(PGE2) can inhibit upregulation of JAK3 protein in naive T
cells and can downregulate its expression in primed cells. Reduction in JAK3 was selective because expression of other tyrosine kinases (JAK1,
p56lck, and p59fyn) and signal transducer and
activator of transcription (STAT)5, which are linked to IL-2 receptor
(IL-2R) signaling pathway, were not affected. Inhibition of JAK3 may be
controlled by intracellular cyclic adenosine monophosphate (cAMP)
levels, as forskolin, a direct activator of adenylate cyclase and
dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP
suppressed JAK3 expression. Moreover, 3-isobutyl-1-methylxanthine
(IBMX), an inhibitor of cAMP phosphodiesterase, potentiated
PGE2-induced suppression of JAK3. In naive T cells, but not
primed T cells, PGE2 and other cAMP elevating agents also
caused a modest reduction in surface expression of the common gamma
chain ( c) that associates with JAK3. The absence of JAK3, but not
IL-2R 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 activity of
STAT5 and poor induction of the c-Myc and c-Jun pathways. In contrast,
IL-2-dependent induction of Bcl-2 was unaffected. These findings
suggest that suppression of JAK3 levels may represent one mechanism by
which PGE2 and other cAMP elevating agents can inhibit
T-cell proliferation.
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