Transgenic over-expression of macrophage migration inhibitory factor renders mice markedly more susceptible to experimental colitis.
Enhanced production of macrophage migration inhibitory factor (MIF) is recognized in patients with inflammatory bowel disease (IBD) and mice with experimental colitis; however, the precise molecular function of MIF in colitis is not fully understood. To further investigate this matter, we examined the pathological features of MIF transgenic mice with dextran sulphate sodium (DSS)-induced colitis. We generated transgenic mice carrying a murine MIF cDNA driven by a cytomegalovirus enhancer and a beta-actin/beta-globin promoter. Mice were orally administered 1-4% DSS in drinking water for 7 days. Clinical disease activity, survival and histological features were evaluated. The level of myeloperoxidase (MPO) activity in the colon tissue was measured to assess neutrophil infiltration. The level of corticosterone in the serum was measured by enzyme linked-immunosorbent assay (ELISA). MIF mRNA and protein were markedly up-regulated in the colon and serum obtained from MIF transgenic mice. The severity of the colitis induced by 1% DSS treatment was markedly higher in MIF transgenic mice than in wild-type mice. We also found that MPO activity was significantly higher in MIF transgenic mice than wild-type mice in response to DSS stimulation. Interestingly, the corticosterone level remained unchanged in MIF transgenic mice. MIF enhances DSS-induced colitis, in part via neutrophil accumulation and inhibition of glucocorticoid bioactivity.
Ohkawara
T
T
Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. tokawara@med.hokudai.ac.jp
Miyashita
K
K
Nishihira
J
J
Mitsuyama
K
K
Takeda
H
H
Kato
M
M
Kondo
N
N
Yamasaki
Y
Y
Sata
M
M
Yoshiki
T
T
Sugiyama
T
T
Asaka
M
M
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index
D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D016264:Dextran Sulfate; D009195:Peroxidase; D003345:Corticosterone