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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigen Presentation / genetics
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Antigen Presentation / immunology
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cells, Cultured
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Corticotropin-Releasing Hormone / antagonists & inhibitors
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Corticotropin-Releasing Hormone / deficiency
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Corticotropin-Releasing Hormone / genetics
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Corticotropin-Releasing Hormone / physiology*
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Cytokines / biosynthesis
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology*
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Glucocorticoids / biosynthesis
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I-kappa B Proteins / metabolism
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Immunity, Innate / genetics
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / physiology*
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Lymphocyte Count
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-KappaB Inhibitor alpha
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Phosphorylation
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Receptors, Antigen, T-Cell / physiology
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Severity of Illness Index
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Spleen / immunology
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Spleen / metabolism
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Spleen / pathology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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Th1 Cells / cytology
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Th1 Cells / immunology
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Th2 Cells / immunology
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Th2 Cells / metabolism
Substances
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Cytokines
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Glucocorticoids
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I-kappa B Proteins
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Inflammation Mediators
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Nfkbia protein, mouse
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Receptors, Antigen, T-Cell
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NF-KappaB Inhibitor alpha
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Corticotropin-Releasing Hormone