Critical role of macrophage migration inhibitory factor activity in experimental autoimmune diabetes.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pivotal role in several immunoinflammatory and autoimmune diseases. In this study we examined the role of MIF in the development of immunoinflammatory diabetes induced in susceptible strains of mice by multiple low doses of streptozotocin. We found that MIF protein was significantly elevated in islet cells during the development of diabetes, and that targeting MIF activity with either neutralizing antibody or the pharmacological inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, markedly reduced clinical and histopathological features of the disease, such as hyperglycemia and insulitis. Lymphocytes from mice treated with the MIF inhibitors exhibited reduction of both islet antigen-specific proliferative responses and adhesive cell-cell interactions. Neutralization of MIF also down-regulated the ex vivo secretion of the proinflammatory mediators, TNF-alpha, interferon-gamma, and nitric oxide, while augmenting that of the antiinflammatory cytokine, IL-10. This study provides the first in vivo evidence for a critical role for MIF in the immune-mediated beta-cell destruction in an animal model of human type 1 diabetes mellitus and identifies a new therapeutic strategy for the prevention and treatment of this disease in humans that is based on the selective inhibition of MIF activity.
Cvetkovic
Ivana
I
Institute for Biological Research Sinisa Stankovic, 29 Novembra 142, 11000 Belgrade, Serbia and Montenegro.
Al-Abed
Yousef
Y
Miljkovic
Djordje
D
Maksimovic-Ivanic
Danijela
D
Roth
Jesse
J
Bacher
Michael
M
Lan
Hui Y
HY
Nicoletti
Ferdinando
F
Stosic-Grujicic
Stanislava
S
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D039481:CD11b Antigen / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009000:Monocytes; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors; D013154:Spleen / Q000473:pathology / Q000503:physiopathology
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000906:Antibodies; D039481:CD11b Antigen; D016207:Cytokines; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D015375:Receptors, Interleukin-2; D009569:Nitric Oxide