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Corticotropin-Releasing Hormone Contributes to the Peripheral Inflammatory Response in Experimental Autoimmune Encephalomyelitis ¹

Christina Benou^2,*, Yue Wang^2,*, Jaime Imitola^*, Lilian VanVlerken, Christina Chandras, Katia P. Karalis and Samia J. Khoury^3,*

^* Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, and Division of Endocrinology, Children’s Hospital and Harvard Medical School, Boston, MA 02115

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- 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 IB 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.

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