Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases.
In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.
Huang
Tien-Yu
TY
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Chu
Heng-Cheng
HC
Lin
Yi-Ling
YL
Lin
Chih-Kung
CK
Hsieh
Tsai-Yuan
TY
Chang
Wei-Kuo
WK
Chao
You-Chen
YC
Liao
Ching-Len
CL
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000401:mortality / Q000517:prevention & control; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control; D008297:Male; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008795:Metronidazole / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013045:Species Specificity; D016019:Survival Analysis; D014302:Trinitrobenzenesulfonic Acid
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D008795:Metronidazole; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; D020782:Matrix Metalloproteinases; D008911:Minocycline