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Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Mucosal+Immunol 2014 ; 7 (3): 521-32 Nephropedia Template TP
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Transcription of ROR?t in Developing Th17 Cells is Regulated by E-Proteins #MMPMID24064669
Zhang F; Fuss IJ; Yang Z; Strober W
Mucosal Immunol 2014[May]; 7 (3): 521-32 PMID24064669show ga
In the present study we investigated the molecular mechanisms regulating the expression of ROR?t, the central factor controlling IL-17 transcription and Th17 differentiation. In key studies we found that cells from mice with major deletions of the E-protein transcription factors, E2A and HEB, display greatly reduced ROR?t/IL-17 expression and that E-protein-deficient mice exhibit greatly diminished IL-17-dependent inflammation in EAE models. In additional studies, we unexpectedly found that cells from mice with deletion of Id3, a protein that inhibits E-protein binding to DNA, display diminished ROR?t/IL-17 expression and mice deficient in this protein exhibit decreased Th17-mediated inflammation in a cell-transfer colitis model. The explanation of these initially paradoxical findings came from studies showing that Id3 deficiency leads to increased IL-4-induced GATA-3 expression, the latter a negative regulator of ROR?t transcription; thus, increased Id3 expression likely has a net positive effect on ROR?t expression via its inhibition of IL-4 production. Finally, we found that both E-proteins and Id3 are up-regulated in tandem by the cytokines that induce Th17 differentiation, TGF-? and IL-6, implying that these transcription factors are critical regulators of Th17 induction.