title: 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.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jeniffer B
authors.initials: JB
authors.lastname: Hernandez
authors.affiliation: Nomis Foundation for Immunobiology and Microbial Pathogenesis Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Chang
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: LeBlanc
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Grimm
authors.affiliation: Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-5156, USA.
authors.forename: John
authors.initials: J
authors.lastname: Le Lay
authors.affiliation: Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-5156, USA.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Nomis Foundation for Immunobiology and Microbial Pathogenesis Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: C492004:Creb1 protein, mouse; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C098680:Il17a protein, mouse; C515932:Il17f protein, mouse; D020381:Interleukin-17; D014157:Transcription Factors; D015232:Dinoprostone