Blockade of macrophage migration inhibitory factor ameliorates experimental autoimmune myocarditis.
Macrophage migration inhibitory factor (MIF) is a cytokine that plays a critical role in the regulation of macrophage effector functions and T-cell activation. However, its role in the pathogenesis of experimental autoimmune myocarditis (EAM) has remained unresolved. In this study, we studied the role of the MIF in EAM. We investigated the expression of MIF in EAM using enzyme-linked immunosorbent assay, Northern blotting, and immunohistochemistry. Moreover, a neutralizing antibody (Ab) to MIF was injected intraperitoneally from day 0 to 20 (experiment 1), or from day 13 to 19 (experiment 2), after the immunization. Disease severity was estimated by the macroscopic and microscopic findings for the heart, heart weight to body weight ratio, and cellular and humoral immune responses on day 21. Enhanced MIF protein and mRNA expression in the heart tissue and an elevated serum MIF concentration were confirmed in EAM. In experiment 1, the anti-MIF Ab treatment markedly inhibited the onset of EAM. Moreover, a significant reduction in disease severity was also achieved even after the delayed anti-MIF Ab treatment in experiment 2. Furthermore, we demonstrated that MIF blockade decreased the expression of VCAM-1, TNF-alpha, and IL-1beta and the migration of T-cells and macrophages in the EAM heart. These results demonstrate an important role of MIF in the pathogenesis of EAM and suggest that MIF blockade may be a promising new strategy for the treatment of myocarditis.
Matsui
Yutaka
Y
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. mlc58949@nifty.com
Okamoto
Hiroshi
H
Jia
Nan
N
Akino
Masatoshi
M
Uede
Toshimitsu
T
Kitabatake
Akira
A
Nishihira
Jun
J
D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D015704:CD4 Antigens / Q000032:analysis / Q000378:metabolism; D016827:CD8 Antigens / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D053331:Ectodysplasins; D015870:Gene Expression; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007375:Interleukin-1 / Q000032:analysis / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D009205:Myocarditis / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D009206:Myocardium / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D053331:Ectodysplasins; D007074:Immunoglobulin G; D007375:Interleukin-1; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1