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Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease

Kithcart, Aaron
http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Integrated Biomedical Sciences.
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.
Caroline Whitacre, PhD (Advisor)
Phillip Popovich (Other)
Michael Racke (Other)
Abhay Satoskar (Other)
Larry Schlesinger (Other)
155 p.
Biomedical Research; Neurology
multiple sclerosis; MS; macrophage migration inhibitory factor; MIF

Recommended Citations

Citations

  • Kithcart, A. (2009). Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146

    APA Style (7th edition)

  • Kithcart, Aaron. Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146.

    MLA Style (8th edition)

  • Kithcart, Aaron. "Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146

    Chicago Manual of Style (17th edition)

osu1244077146
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© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.