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.
Interleukin-4 is an important cytokine for the regulation of atopic asthma and other allergic diseases. Our application proposes to study the role of one Interleukin-4 -inducible gene, called NFIL3 gene, that appears to be essential for allergic immune responses in mice.
|Phong, Binh L; Avery, Lyndsay; Sumpter, Tina L et al. (2015) Tim-3 enhances FcÎµRI-proximal signaling to modulate mast cell activation. J Exp Med 212:2289-304|
|Gorman, Jacob V; Starbeck-Miller, Gabriel; Pham, Nhat-Long L et al. (2014) Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J Immunol 192:3133-42|
|Duong, Khanh L; Das, Satyabrata; Yu, Shuyang et al. (2014) Identification of hematopoietic-specific regulatory elements from the CD45 gene and use for lentiviral tracking of transplanted cells. Exp Hematol 42:761-72.e1-10|
|Gorman, Jacob V; Colgan, John D (2014) Response to Comment on "Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection". J Immunol 193:467-8|
|Gorman, Jacob V; Colgan, John D (2014) Regulation of T cell responses by the receptor molecule Tim-3. Immunol Res 59:56-65|
|Sharma, S; Sheehy, T; Kolonel, L N (2013) Contribution of meat to vitamin Bâ‚â‚‚, iron and zinc intakes in five ethnic groups in the USA: implications for developing food-based dietary guidelines. J Hum Nutr Diet 26:156-68|
|Curtiss, Miranda L; Gorman, Jacob V; Businga, Thomas R et al. (2012) Tim-1 regulates Th2 responses in an airway hypersensitivity model. Eur J Immunol 42:651-61|
|Hostager, Bruce S; Kashiwada, Masaki; Colgan, John D et al. (2011) HOIL-1L interacting protein (HOIP) is essential for CD40 signaling. PLoS One 6:e23061|
|Kashiwada, Masaki; Pham, Nhat-Long L; Pewe, Lecia L et al. (2011) NFIL3/E4BP4 is a key transcription factor for CD8Î±âº dendritic cell development. Blood 117:6193-7|
|Kashiwada, Masaki; Cassel, Suzanne L; Colgan, John D et al. (2011) NFIL3/E4BP4 controls type 2 T helper cell cytokine expression. EMBO J 30:2071-82|
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