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*
Department of Medicine, Hospital for Special Surgery, Cornell University Medical College,
Cornell/Rockefeller/Sloan-Kettering Tri-Institutional M.D.-Ph.D. Program, and
Graduate Program in Immunology, Cornell University Graduate School of Medical Sciences, New York, NY 10021
IL-2 activates several distinct signaling pathways that are
important for T cell activation, proliferation, and differentiation
into both Th1 and Th2 phenotypes. IL-4, the major cytokine that
promotes differentiation of Th2 cells, has been shown to block
signaling of the Th1-promoting cytokine IL-12. As IL-2 synergizes with
IL-12 in promoting Th1 differentiation, the effects of IL-4 on IL-2
signal transduction were investigated. IL-4 suppressed activation of
DNA binding and tyrosine phosphorylation of the transcription factor
Stat5 by IL-2, and suppressed the expression of the IL-2-inducible
genes CD25, CIS, the PGE2 receptor, and cytokine responsive
(CR) genes CR1 and CR8. Activation of Stat5 by cytokines that share a
common 
receptor subunit, IL-2, IL-7, and IL-15, was suppressed by
preculture in IL-4. Activation of the Jak1 and Jak3 kinases that are
proximal to Stat5 in the IL-2-Jak-STAT signaling pathway was
suppressed, and this correlated with inhibition of IL-2Rß subunit
expression. In contrast to suppression of Stat5, proliferative
responses to IL-2 were augmented in IL-4-cultured cells, and activation
of proliferative pathways leading to activation of mitogen activated
protein kinases, induction of expression of Myc, Fos, Pim-1, and cyclin
D3, and decreased levels of the cyclin-dependent kinase inhibitor p27
were intact. These results identify molecular mechanisms underlying
interactions between IL-4 and IL-2 in T cells and demonstrate that one
mechanism of regulation of IL-2 activity is selective and differential
modulation of signaling pathways.
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