The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation.

Abstract	Following their activation in response to inflammatory signals, innate immune cells secrete T-cell-polarizing cytokines that promote the differentiation of naive CD4 T cells into T helper (Th) cell subsets. Among these, Th17 cells play a prominent role in the development of a number of autoimmune diseases. Although regarded primarily as an immunosuppressant signal, cAMP has been found to mediate pro-inflammatory effects of macrophage-derived prostaglandin E2 (PGE2) on Th17 cells. Here we show that PGE2 enhances Th17 cell differentiation via the activation of the CREB co-activator CRTC2. Following its dephosphorylation, CRTC2 stimulates the expression of the cytokines IL-17A and IL-17F by binding to CREB over both promoters. CRTC2-mutant mice have decreased Th17 cell numbers, and they are protected from experimental autoimmune encephalitis, a model for multiple sclerosis. Our results suggest that small molecule inhibitors of CRTC2 may provide therapeutic benefit to individuals with autoimmune disease.
Authors	Jeniffer B Hernandez, Christina Chang, Mathias LeBlanc, David Grimm, John Le Lay, Klaus H Kaestner, Ye Zheng, Marc Montminy
Journal	Nature communications (Nat Commun) Vol. 6 Pg. 7216 (Jun 02 2015) ISSN: 2041-1723 [Electronic] England
PMID	26031354 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Creb1 protein, mouse Crtc2 protein, mouse Cyclic AMP Response Element-Binding Protein Il17a protein, mouse Il17f protein, mouse Interleukin-17 Transcription Factors Dinoprostone
Topics	Animals Blotting, Western Brain (immunology) CD4-Positive T-Lymphocytes Cell Differentiation (immunology) Chromatin Immunoprecipitation Cyclic AMP Response Element-Binding Protein (immunology, metabolism) Dinoprostone (pharmacology) Encephalomyelitis, Autoimmune, Experimental (genetics, immunology) HEK293 Cells Humans Interleukin-17 (genetics, immunology) Lymphocyte Activation (immunology) Mice Promoter Regions, Genetic Real-Time Polymerase Chain Reaction Spinal Cord (immunology) Th17 Cells (immunology) Transcription Factors (drug effects, genetics, immunology)

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