): 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI042310-01A1
Application #
2692921
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1998-06-01
Project End
2003-04-30
Budget Start
1998-06-01
Budget End
1999-04-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Picower Institute for Medical Research
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Sparkes, Amanda; De Baetselier, Patrick; Roelants, Kim et al. (2017) The non-mammalian MIF superfamily. Immunobiology 222:473-482
Brocks, Tania; Fedorchenko, Oleg; Schliermann, Nicola et al. (2017) Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin. FASEB J 31:526-543
Kim, Bong-Sung; Ott, Veronica; Boecker, Arne Hendrick et al. (2017) The Effect of Antiseptics on Adipose-Derived Stem Cells. Plast Reconstr Surg 139:625-637
Meza-Romero, Roberto; Benedek, Gil; Jordan, Kelley et al. (2016) Modeling of both shared and distinct interactions between MIF and its homologue D-DT with their common receptor CD74. Cytokine 88:62-70
Yao, Jie; Leng, Lin; Sauler, Maor et al. (2016) Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. J Clin Invest 126:732-44
Kim, Bong-Sung; Stoppe, Christian; Grieb, Gerrit et al. (2016) The clinical significance of the MIF homolog d-dopachrome tautomerase (MIF-2) and its circulating receptor (sCD74) in burn. Burns 42:1265-76
Meza-Romero, Roberto; Benedek, Gil; Leng, Lin et al. (2016) Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. Metab Brain Dis 31:249-55
Das, Rituparna; Loughran, Kerry; Murchison, Charles et al. (2016) Association between high expression macrophage migration inhibitory factor (MIF) alleles and West Nile virus encephalitis. Cytokine 78:51-4
Stoppe, Christian; Rex, Steffen; Goetzenich, Andreas et al. (2015) Interaction of MIF Family Proteins in Myocardial Ischemia/Reperfusion Damage and Their Influence on Clinical Outcome of Cardiac Surgery Patients. Antioxid Redox Signal 23:865-79
Bick, Johanna; Nguyen, Victoria; Leng, Lin et al. (2015) Preliminary associations between childhood neglect, MIF, and cortisol: potential pathways to long-term disease risk. Dev Psychobiol 57:131-9

Showing the most recent 10 out of 103 publications