Treatment with bindarit, an inhibitor of MCP-1 synthesis, protects mice against trinitrobenzene sulfonic acid-induced colitis.
OBJECTIVE
Chemokines play a fundamental role in trafficking and activation of leukocytes in colonic inflammation. We investigated the ability of bindarit, an inhibitor of monocyte chemoattractant protein-1 (MCP-1/CCL2) synthesis, to inhibit chemokine production by human intestinal epithelial cells (HT-29) and its effect in trinitro-benzene sulfonic acid (TNBS)-induced colitis in mice.


METHODS
HT-29 cells were incubated with bindarit in the presence of TNF-alpha/IFN-gamma and 24 h later supernatants were collected for MCP-1, IL-8 and RANTES measurement. A 1 mg enema of TNBS was given to BALB/c mice, and bindarit (100 mg/kg) was orally administered twice daily starting from two days before colitis induction. Weight loss, histology, and MCP-1 level and myeloperoxidase (MPO) activity in colon extracts were assessed.


RESULTS
In HT-29 cells, bindarit concentration-dependently and selectively inhibited MCP-1 secretion (as well as mRNA expression) primed by TNF-alpha/IFN-gamma. Moreover treatment with bindarit reduced clinical and histopathological severity of TNBS-induced colitis. These effects were associated with significant inhibition of MCP-1 and MPO in colon extracts.


CONCLUSIONS
Bindarit exhibits a potent bioactivity in reducing leukocyte infiltration, down-regulating MCP-1 synthesis, and preventing the development of severe colitis in a mice model of TNBS-induced colitis. These observations suggest a potential use of MCP-1 synthesis blockers in intestinal inflammation in humans.
Bhatia
M
M
Cardiovascular Biology Group, Department of Pharmacology, c/o Centre for Life Science, #03-02 National University of Singapore, 28 Medical Dr., Singapore 117456, Malaysia. mbhatia@nus.edu.sg
Landolfi
C
C
Basta
F
F
Bovi
G
G
Ramnath
R Devi
RD
de Joannon
A Capezzone
AC
Guglielmotti
A
A
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D007191:Indazoles / Q000378:metabolism / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011422:Propionates / Q000378:metabolism / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D018932:Chemokine CCL2; D007191:Indazoles; D011422:Propionates; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; C079489:bindarit