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 ulcerat ive (UC) and Crohn's colitis. We examined the local and systemic appea rance of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in an ex perimental animal model of inflammatory bowel disease. Colitis was ind uced in CBA/J mice by adding dextran sulfate sodium (DSS), 5% (wt/vol) , to their water. DSS-induced colitis is a reproducible animal model f or evaluating the role of cytokines in the pathology of colitis. Anima ls were weighed daily, and stools were checked for the presence of blo od. Groups of mice were killed daily, blood samples were taken for mea surement of plasma cytokine levels, and colonic samples were taken for histology and measurement of TNF and IL-6 bioactivity. Mice fed DSS d eveloped colitis with bloody diarrhea, weight loss, and colonic inflam mation 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 contras t, plasma IL-6 was detectable from days 4 to 9 and was detectable in c olonic tissue in only a few (two of four) terminally ill animals on da y 9. Animals were injected with a neutralizing, polyclonal anti-TNF an tiserum that maintained high in vivo neutralizing titers for greater t han or equal to 48 h. This anti-TNF antiserum failed to block or modif y the severity of colitis induced by DSS. Failure to detect local or s ystemic TNF and failure to prevent colonic inflammation with anti-TNF antiserum showed that TNF is not an inflammatory mediator in DSS-induc ed murine colitis.