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Interferon Regulatory Factor 4 (IRF4) Interacts with NFATc2 to Modulate Interleukin 4 Gene Expression

Proteins of the nuclear factor of activated T cells (NFAT) family of transcription factors are critical for lymphocyte activation in the immune system. In particular, NFATs are important regulators of inducible IL-4 gene expression. Interferon regulatory factor 4 (IRF4) is an immune system–restricted interferon regulatory factor that is required for lymphocyte activation, but its molecular functions in the T lineage remain to be elucidated. We demonstrate that IRF4 potently synergizes with NFATc2 to specifically enhance NFATc2-driven transcriptional activation of the IL-4 promoter. This function is dependent on the physical interaction of IRF4 with NFATc2. IRF4 synergizes with NFATc2 and the IL-4–inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production. Furthermore, naïve T helper cells from mice lacking IRF4 are compromised severely for the production of IL-4 and other Th2 cytokines. The identification of IRF4 as a partner for NFATc2 in IL-4 gene regulation provides an important molecular function for IRF4 in T helper cell differentiation. IRF4 NFAT IL-4 transcriptional regulation interaction Footnotes ↵ * Abbreviations used in this paper: CsA, cyclosporin A; HA, hemagglutinin; HRP, horseradish peroxidase; IRF4, interferon regulatory factor 4; NFAT, nuclear factor of activated T cells; NIP45, NFAT-interacting protein 45. Submitted: 28 June 2001 Accepted: 1 March 2002 Revision received 15 February 2002 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

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