IL-4 Signal Transduction

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DESCRIPTION (provided by applicant): Cytokines are important modulators of the immune response that underlies the inflammatory component of atopic asthma and other allergic diseases. Interleukin-4 is an important cytokine for the regulation of allergic immune responses. However, the molecular mechanisms that regulate the response of cells to IL-4 are still not completely defined. IL-4 plays an important role in B cell biology. It can regulate B cell differentiation. For example, IL-4 induces immunoglobulin heavy chain class switching to IgE and IgG1 in mice (IgE and IgG4 in humans) by inducing germline immunoglobulin heavy chain transcription. It also induces expression of CD23 and MHC class II. Further understanding of the mechanisms by which IL-4 mediates these biologic responses may lead to novel mechanisms for therapeutic intervention and control of allergy. To define how different signaling pathways activated by IL-4 regulate gene transcription, we identified many differentially expressed genes by IL-4 stimulation by microarray analysis. NFIL3 (nuclear factor, interleukin 3 regulated) is the most strongly induced transcription factor by IL-4 stimulation in a STAT6-dependent manner. To analyze the role of NFIL3 in immune system, we have generated NFIL3-deficient mice. NFIL3-deficient mice showed greatly impaired IgE production in response to antigen. NFIL3-deficient B cells fail to produce IgE but not IgG1 in response to LPS plus IL-4. These defects may be due to the reduced production of immunoglobulin heavy chain germline epsilon transcripts in the absence of NFIL3. Moreover, NFIL3 KO mice sensitized and challenged with ovalbumin showed reduced airway hyper-responsiveness when compared to wild type mice. Therefore, we hypothesize that NFIL3 is a critical regulator for IgE production and airway hyper-responsiveness. We propose to determine the molecular mechanisms by which NFIL3 regulates IgE production and the production of airway hyper-responsiveness.