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A small‐molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease
Author(s) -
Kithcart Aaron P.,
Cox Gina M.,
Sielecki Thais,
Short Abigail,
Pruitt James,
Papenfuss Tracey,
Shawler Todd,
Gienapp Ingrid,
Satoskar Abhay R.,
Whitacre Caroline C.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-162347
Subject(s) - macrophage migration inhibitory factor , multiple sclerosis , experimental autoimmune encephalomyelitis , proinflammatory cytokine , immunology , cytokine , medicine , immune system , encephalomyelitis , population , macrophage , inflammation , biology , in vitro , biochemistry , environmental health
Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) characterized by demyelination and axon loss. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be elevated in the cerebrospinal fluid of patients during relapses. The purpose of this study was to evaluate a new small‐molecule inhibitor of MIF and its ability to reduce the severity of an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We utilized 2 structurally related isoxazolines, which show in vitro inhibition of MIF tautomerase activity. We found that administration of an inhibitor of MIF to mice with established EAE immediately reduced the severity of clinical signs and expanded a population of regulatory T lymphocytes. We also noted that the inhibitor reduced relapses of disease in a relapsing/remitting model of EAE. An analysis of leukocyte migration into the brain revealed that administration of inhibitor reduced entry of these cells. No effects on inflammatory cytokine production or T‐cell activation in the periphery were noted. From these studies, we conclude that a small‐molecule inhibitor of MIF reduces the severity of EAE and prevents access of immune cells into the CNS, which could be of therapeutic relevance to MS.—Kithcart, A. P., Cox, G. M., Sielecki, T., Short, A., Pruitt, J., Papenfuss, T., Shawler, T., Gienapp, I., Satoskar, A. R., Whitacre, C. C. A small‐molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease. FASEB J . 24, 4459–4466 (2010). www.fasebj.org