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Nat Commun. 2015 Jun 2;6:7216. doi: 10.1038/ncomms8216.

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

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Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nomis Foundation for Immunobiology and Microbial Pathogenesis Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-5156, USA.


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.

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