Interferon-gamma (IFN-γ)- and tumour necrosis factor (TNF)-induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)-induced colitis in mice

Abstract

SUMMARY Excess nitric oxide formation caused by the activity of the inducible nitric oxide synthase has been implicated as a toxic effector molecule in the pathogenesis of experimental colitis and inflammatory bowel disease. It was therefore investigated whether inhibition of this synthase or the cytokines TNF and IFN-γ, inducers of nitric oxide synthase, had effects on chronic colitis in mice. Chronic colitis was induced in mice by repeated feeding of DSS. Cytokines were neutralized by treatment with MoAbs and nitric oxide synthase was inhibited by aminoguanidine. The degree of colonic inflammation was assessed by a histological score and colon length. Aminoguanidine treatment reduced nitric oxide activity by 60% (P = 0.0004), the histological score by 31% (P = 0.005) and increased colon length by 1.4 cm (P = 0.002). Neutralization of TNF and IFN-γ resulted in increased colon length (0.7 cm, P = 0.07 and 0.8 cm, P = 0.03), improved histological score (19%, P = 0.045 and 25%, P = 0.013), and reduced nitric oxide activity (31%, P = 0.07 and 54%, P = 0.004) compared with controls. The combination of anti-cytokine treatments had additive effects. TNF and IFN-γ are involved in perpetuation of chronic DSS-induced colitis, and induction of excessive nitric oxide activity could be their common effector mechanism.