Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease

Bibliographic Details
Main Author:	Kithcart, Aaron
Language:	English
Published:	The Ohio State University / OhioLINK 2009
Subjects:	Biomedical Research Neurology multiple sclerosis MS macrophage migration inhibitory factor MIF
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-osu12440771462021-08-03T05:56:21Z Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease Kithcart, Aaron Biomedical Research Neurology multiple sclerosis MS macrophage migration inhibitory factor MIF Multiple sclerosis represents one the most common and complex syndromes of the family of autoimmune diseases. Affecting more than 2.4 million worldwide in the second and third decades of life, it is the primary cause of non-traumatic disability in the United States. Sensory and motor neuron loss follows the demyelination of axons in the brain and spinal cord after autoreactive T lymphocytes gain access to the central nervous system and mediate an inflammatory reaction. Thus, most current therapies in multiple sclerosis seek to suppress the immune system in order to slow progression. Several cytokines have been shown to be involved in the pathogenesis of autoimmune diseases, including multiple sclerosis. We have focused on macrophage migration inhibitory factor, a ubiquitously expressed proinflammatory cytokine that has been described in a number of syndromes. Utilizing an MIF knockout model of EAE in the C57Bl/6 strain of mice, we show that MIF is required for susceptibility to EAE. MIF knockout mice are protected with a decreased incidence of disease and lower clinical scores. Additionally, we show that an inhibitor of MIF is therapeutic during ongoing disease. Administration of an MIF inhibitor reduced clinical scores. We propose several mechanisms of MIF that mediate inflammation. First, MIF inhibits the expansion of CD4+CD25+Foxp3+ regulatory T lymphocytes. This population of cells is found in higher numbers after immunization in MIF knockout and inhibitor-treated mice. CD4+CD25+Foxp+ regulatory T lymphocytes are protective during EAE through contact inhibition with autoreactive lymphocytes and the production of IL-10. Second, we propose that MIF mediates leukocyte migration into the brain and spinal cord. We show that MIF knockout mice have profoundly reduced inflammation and the administration of an inhibitor of MIF prevents new migration into the brain. Furthermore, MIF knockout recipient mice were universally protected following adoptive transfer of autoreactive lymphocytes. Finally, MIF regulates the synthesis of testosterone. MIF knockout mice have a four fold higher level of testosterone than wild type mice. Testosterone is an immunosuppressive hormone, and gonadectomy of MIF knockout mice greatly increased the incidence of EAE. We propose that MIF mediates inflammation via different mechanisms depending on the timing of disease. Inhibition of testosterone in naïve mice enhances susceptibility to disease. Later changes during inflammation, including inhibition of regulatory T cell differentiation and facilitation of migration into peripheral tissues allows the progression of disease. We propose that targeting MIF during multiple sclerosis could be therapeutic through novel regulation of multiple aspects of inflammation. 2009-09-08 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146 http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Biomedical Research Neurology multiple sclerosis MS macrophage migration inhibitory factor MIF
spellingShingle	Biomedical Research Neurology multiple sclerosis MS macrophage migration inhibitory factor MIF Kithcart, Aaron Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease
author	Kithcart, Aaron
author_facet	Kithcart, Aaron
author_sort	Kithcart, Aaron
title	Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease
title_short	Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease
title_full	Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease
title_fullStr	Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease
title_full_unstemmed	Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease
title_sort	macrophage migration inhibitory factor: a key mediator of inflammatory disease
publisher	The Ohio State University / OhioLINK
publishDate	2009
url	http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146
work_keys_str_mv	AT kithcartaaron macrophagemigrationinhibitoryfactorakeymediatorofinflammatorydisease
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Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease

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