Phenyl methimazole suppresses dextran sulfate sodium-induced murine colitis.
Ulcerative colitis is an autoimmune-inflammatory disease characterized by abnormally increased expression of Toll-like receptor-4 (TLR4) in colonic epithelial cells, increased production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-1beta, IL-6, IL-12), chemokines (e.g., IP-10), and endothelial cell adhesion molecules (e.g., VCAM-1), plus enhanced leukocyte infiltration into colonic interstitium. Previously, we have shown that phenyl methimazole (C10) markedly decreases virally-induced TLR-3 expression and signaling and potently inhibits both TNF-alpha-induced VCAM-1 expression and the resultant leukocyte-endothelial cell adhesion. In this study we probed the hypothesis that C10 is efficacious in a TLR-4- and VCAM-1-associated murine model [the dextran sulfate sodium (DSS) model] of human colitis. C10 was administered intraperitoneally coincident with or after DSS treatment was initiated. Macroscopic colon observations revealed that C10 significantly reversed DSS-induced shortening of the colon (P<0.05) and reduced the presence of blood in the colon. Histological analyses of colonic tissues revealed that C10 distinctly attenuated both DSS-induced edema as well as leukocyte infiltration in the colonic mucosa and resulted in pronounced protection against DSS-induced crypt damage (P<0.001). Northern blot analyses and immunohistochemistry of colonic tissue revealed that C10 markedly diminished DSS-induced expression of pertinent inflammatory mediators: TNF-alpha, IL-1beta, IL-6, IL-12, IP-10, TLR-4 and VCAM-1. Most importantly, C10 significantly improved survival and protected mice against DSS-induced colitic-death: 75% by comparison to 12.5% with identical treatment with DMSO-control (log rank test: P=0.005). These results provide direct evidence that C10 suppresses DSS-induced colitis by inhibiting expression of key inflammatory mediators and leukocyte infiltration, and is a potentially attractive therapeutic for colitis.
Benavides
Uruguaysito
U
The Department of Biomedical Sciences, College of Osteopathic Medicine, Edison Biotechnology Institute, Ohio University, Athens, OH 45701, United States.
Gonzalez-Murguiondo
Mariana
M
Harii
Norikazu
N
Lewis
Christopher J
CJ
Sakhalkar
Harshad S
HS
Deosarkar
Sudhir P
SP
Kurjiaka
David T
DT
Dagia
Nilesh M
NM
Goetz
Douglas J
DJ
Kohn
Leonard D
LD
D000818:Animals; D015152:Blotting, Northern; D003093:Colitis, Ulcerative / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008713:Methimazole / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D013871:Thiones / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology*
D016207:Cytokines; D013871:Thiones; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; C489637:phenyl methimazole; D008713:Methimazole; D016264:Dextran Sulfate