Interleukin-4 (IL-4) plays an important role in regulating the immune response. This cytokine does so by binding to cell surface receptor complexes consisting of the IL-4 binding chain (IL-4R) and the common gamma chain and eliciting a signal transduction cascade that ultimately leads to a specific biologic response. We have recently shown that a sequence motif found in the cytoplasmic domain of the IL-4R, termed the I4R-motif, makes an important contribution to the tyrosine phosphorylation of cellular substrates and to the proliferative response to IL-4. In addition, several downstream tyrosine residues have been implicated in the IL-4 induced activation of a latent transcription factor. These recent studies on the mechanisms of signal transduction used by the IL-4 receptor complex provide the starting point for our long-term objective, to determine the molecular mechanisms of IL-4-induced regulation of lymphocytes. Our hypothesis is that the sequence within the IL-4R cytoplasmic domain direct the signaling pathways activated by IL-4 and determine the """"""""specificity"""""""" of the IL-4 signal. The major goal of this proposal is to examine the significance and function of the I4R-motif in signaling by the IL-4R. To achieve this goal, we plan to identify the residues within the I4R motif that are critical for IL-4 signal transduction by site-directed mutagenesis. We will establish the contribution of the I4R-motif in determining IL-4-specific responses by transplanting the I4R-motif and other sequences unique to the IL-4R to the cytoplasmic domain of a different cytokine receptor that uses the gamma-c, the IL-2 receptor. We will test the ability of these chimeric receptors to signal IL-4-specific responses, such as the activation of the insulin receptor substrate -1 (IRS-1) and the induction CD23 and C-epsilon, in transfected cell lines treated with IL-2. Finally we plan to examine the effects of IL-4 on the regulators of cell cycle, including the cyclins, cyclin-dependent kinases (cdk), and the cdk inhibitor p27, and the effects of IL-4 on the prevention of apoptosis. Given the profound effects of IL-4 on immune regulation, an understanding of the mechanism of its actions could aid in the development of strategies to regulate immune responses elicited by vaccines or by environmental allergens.
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