FR167653, a potent suppressant of interleukin-1 and tumor necrosis factor-α production, ameliorates colonic lesions in experimentally induced acute colitis1.

AbstractBackground: Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are believed to play a significant role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-1 and TNF-α possess overlapping and synergetic activities inducing the production in cascade of other cytokines, adhesion molecules, arachidonic acid metabolites, as well as activating immune and non-immune cells. FR167653 (C24H18FN5O2.H2SO4.H2O) is a newly synthesized organic compound with a potent inhibitory effect on IL-1β and TNF-α production. We hypothesized that the suppression of IL-1 and TNF-α induced by FR167653 could effectively attenuate experimentally induced colonic damage. Methods: Colonic lesions were induced in male Sprague–Dawley rats (250–300 g) by intrarectal instillation of 4% acetic acid. The effect of FR167653 administration at 1.0, 1.5, 2.5 mg/kg per 6 h subcutaneously on acetic acid-induced colonic damage was assessed. The lesion area, microscopic findings, colonic and serum levels of TNF-α and IL-1β were also evaluated. Results: Treatment with FR167653 at 1.5 and 2.5 mg/kg per 6 h was able to ameliorate the gross macroscopic appearance of colonic lesions significantly, as well as ameliorate the lesion area induced by acetic acid. Colonic mucosal TNF-α and IL-1β levels of rats treated with FR167653 showed significant decrease in a dose-dependent fashion compared with the control group. In the same manner, serum TNF-α of rats treated with FR167653 was significantly lower than that of respective controls. Conclusions: Subcutaneous administration of FR167653 was able to ameliorate the acute changes induced by acetic acid instillation in a dose-dependent manner. This is the first report to evaluate the dual inhibition of the production of IL-1 and TNF-α, offered by FR167653, in acute experimental colitis.... [ABSTRACT FROM AUTHOR]