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

Excess nitric oxide formation caused by the activity of the inducible nitri c oxide synthase has been implicated as a toxic effector molecule in the pa thogenesis of experimental colitis and inflammatory bowel disease. It was t herefore investigated whether inhibition of this synthase or the cytokines TNF and IFN-gamma, inducers of nitric oxide synthase, had effects on chroni c 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 inflammati on was assessed by a histological score and colon length. Aminoguanidine tr eatment 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-gamma 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 = 0.0 7 and 54%, P = 0.004) compared with controls. The combination of anti-cytok ine treatments had additive effects. TNF and IFN-gamma are involved in perp etuation of chronic DSS-induced colitis, and induction of excessive nitric oxide activity could be their common effector mechanism.