Amelioration of dextran sulfate sodium-induced colitis by anti-macrophage migration inhibitory factor antibody in mice.
OBJECTIVE
We investigated the effects of macrophage migration inhibitory factor (MIF) antibodies in experimental colitis-induced dextran sulfate sodium (DSS) and trinitrobenzenesulfonic acid (TNBS) and examined whether plasma levels of MIF were elevated in patients with inflammatory bowel disease (IBD).


METHODS
BALB/c or C57BL/6 mice were fed 4% DSS in their drinking water for up to 7 days with and without administration of an anti-MIF antibody every 2 days. The severity of inflammation in the cecum and colon was assessed by clinical signs and histologic scoring. Tissue levels of MIF, tumor necrosis factor (TNF)-alpha, interferon gamma (IFN-gamma), interleukin (IL)-4, and matrix metalloproteinase (MMP)-13 messenger RNA (mRNA) were measured. The effects of anti-MIF antibody on chronic colitis induced by TNBS was assessed in BALB/c mice. Plasma MIF concentrations were assayed in patients with Crohn's disease, ulcerative colitis, and healthy controls.


RESULTS
During DSS-induced colitis, colonic MIF mRNA expression was increased. Clinical signs and histopathologic features were significantly improved in animals given anti-MIF antibody. DSS-induced up-regulation of colonic TNF-alpha and IFN-gamma were significantly suppressed in animals given the anti-MIF antibody. Colonic IL-4 was decreased during DSS but restored to baseline by the anti-MIF antibody. The anti-MIF antibody prevented MMP-13 up-regulation by DSS and ameliorated TNBS colitis. Plasma MIF was elevated in patients with Crohn's disease or ulcerative colitis compared with healthy controls.


CONCLUSIONS
We conclude that anti-MIF antibodies reduce the severity of experimental colitis and limit the up-regulation of Th1-type cytokines. Anti-MIF antibodies are of potential therapeutic use in IBD.
Ohkawara
Tatsuya
T
Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Nishihira
Jun
J
Takeda
Hiroshi
H
Hige
Shuhei
S
Kato
Mototsugu
M
Sugiyama
Toshiro
T
Iwanaga
Toshihiko
T
Nakamura
Hideki
H
Mizue
Yuka
Y
Asaka
Masahiro
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002432:Cecum / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology*; D003093:Colitis, Ulcerative / Q000097:blood; D003106:Colon / Q000378:metabolism; D003424:Crohn Disease / Q000097:blood; D016264:Dextran Sulfate; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000906:Antibodies; D008263:Macrophage Migration-Inhibitory Factors; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse