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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI038985-05
Application #
6169309
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Plaut, Marshall
Project Start
1996-05-01
Project End
2001-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
5
Fiscal Year
2000
Total Cost
$96,385
Indirect Cost
Name
American National Red Cross
Department
Type
DUNS #
003255213
City
Washington
State
DC
Country
United States
Zip Code
20006
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Myneni, Srinivas R; Settem, Rajendra P; Connell, Terry D et al. (2011) TLR2 signaling and Th2 responses drive Tannerella forsythia-induced periodontal bone loss. J Immunol 187:501-9

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