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

Background: Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are believed to play a significant role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-1 and TNF-alpha 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-1beta and TNF-alpha production. We hypothesized that the suppression of IL-1 and TNF-alpha 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-alpha and IL-1beta 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-alpha and IL-1beta 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-alpha 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-alpha, offered by FR167653, in acute experimental colitis. Further studies are necessary to evaluate FR167653's efficacy and safety on long-term conditions. (C) 2001 Blackwell Science Asia Pry Ltd.