): The development of an inflammatory response is an essential part of the host defense against infection. Cytokines function in this process by recruiting and activating the critical effector cells that serve to eliminate the source of infection and preserve host integrity. Glucocorticoid hormones, produced by the adrenal glands, are important endogenous modulators of immuity and can exert a powerful inhibitory effect on the development of an inflammatory reaction. Recent work has led to the concept that the mediator macrophage migration inhibitory factor ( MIF ) can act as a physiological counter-regulator of glucocorticoid action within the immune system. MIF has the unique property of being released from macrophages and T cells in response to glucocorticoids and, once released, can """"""""override"""""""" or counter-regulate the inhibitory effect of glucocorticoids on inflammatory cytokine production. The overall aim of this grant proposal is to examine more closely the role of MIF in host defenses and to define the molecular basis of the MIF/glucocorticoid interaction.
The specific aims are to: (1) Characterize the role of MIF in the host responses to infection. The expression of MIF will be examined in established experimental models of infection that produce different clinical courses. These studies will investigate the influence of MIF on the course and outcome of these diseases, and on the production of inflammatory mediators and glucocorticoid hormones. A newly developed ELISA for MIF will be utilized to obtain information on circulating MIF levels in human disease using samples obtained from a clinically-defined group of patients with infection and septicemia. (2) Define the mechanism(s) of the MIF/glucocorticoid interaction. The applicant will investigate whether MIF modulates the expression of the isoforms of the glucocorticoid receptor or alters their function, inhibits steroid induction of the protein IkB, an inhibitor of NF-kB, and upregulates the transcription factors NF-kB and AP-1, which are implicated in the transactivation of the genes of important immune mediators. These studies will lead to new information on the role of the MIF/glucocorticoid system in the host defense against infection.
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