ANTISERUM TO TUMOR-NECROSIS-FACTOR AND FAILURE TO PREVENT MURINE COLITIS

Cytokines regulate many aspects of disease and have been implicated as mediators of the inflammatory reactions in patients with both ulcerative (UC) and Crohn's colitis. We examined the local and systemic appearance of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in an experimental animal model of inflammatory bowel disease. Colitis was induced in CBA/J mice by adding dextran sulfate sodium (DSS), 5% (wt/vol), to their water. DSS-induced colitis is a reproducible animal model for evaluating the role of cytokines in the pathology of colitis. Animals were weighed daily, and stools were checked for the presence of blood. Groups of mice were killed daily, blood samples were taken for measurement of plasma cytokine levels, and colonic samples were taken for histology and measurement of TNF and IL-6 bioactivity. Mice fed DSS developed colitis with bloody diarrhea, weight loss, and colonic inflammation by days 5-9. Histologic examination of the colons showed focal crypt destruction and ulceration. In mice with DSS-induced colitis no TNF was detectable in colonic tissue extracts or in plasma. In contrast, plasma IL-6 was detectable from days 4 to 9 and was detectable in colonic tissue in only a few (two of four) terminally ill animals on day 9. Animals were injected with a neutralizing, polyclonal anti-TNF antiserum that maintained high in vivo neutralizing titers for greater than or equal to 48 h. This anti-TNF antiserum failed to block or modify the severity of colitis induced by DSS. Failure to detect local or systemic TNF and failure to prevent colonic inflammation with anti-TNF antiserum showed that TNF is not an inflammatory mediator in DSS-induced murine colitis.