title: Corticotropin-releasing hormone contributes to the peripheral inflammatory response in experimental autoimmune encephalomyelitis.
abstract: Peripheral corticotropin-releasing hormone (CRH) is thought to have proinflammatory effects. We used the model of experimental autoimmune encephalomyelitis (EAE) to study the role of CRH in an immune-mediated disease. We showed that CRH-deficient mice are resistant to EAE, with a decrease in clinical score as well as decreased cellular infiltration in the CNS. Furthermore, Ag-specific responses of primed T cells as well as anti-CD3/anti-CD28 TCR costimulation were decreased in crh(-/-) mice with decreased production of Th1 cytokines and increased production of Th2 cytokines. Wild-type mice treated in vivo with a CRH antagonist showed a decrease in IFN-gamma production by primed T cells in vitro. This effect of CRH is independent of its ability to increase corticosterone production, because adrenalectomized wild-type mice had similar disease course and severity as control mice. We found that IkappaBalpha phosphorylation induced by TCR cross-linking was decreased in crh(-/-) T cells. We conclude that peripheral CRH exerts a proinflammatory effect in EAE with a selective increase in Th1-type responses. These findings have implications for the treatment of Th1-mediated diseases such as multiple sclerosis.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Benou
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: Lilian
authors.initials: L
authors.lastname: VanVlerken
authors.forename: Christina
authors.initials: C
authors.lastname: Chandras
authors.forename: Katia P
authors.initials: KP
authors.lastname: Karalis
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D005938:Glucocorticoids / Q000096:biosynthesis; D020672:I-kappa B Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012720:Severity of Illness Index; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; C000606205:Nfkbia protein, mouse; D011948:Receptors, Antigen, T-Cell; D000072000:NF-KappaB Inhibitor alpha; D003346:Corticotropin-Releasing Hormone