We investigated the effects of marimastat, an inhibitor of TNF-α converting enzyme and matrix metalloproteinases, and anti-TNF-α antibodies on a murine model for sepsis, and on arthritis in human TNF-α transgenic mice. Marimastat (25-200mg/kg) inhibited lipopolysaccharide (LPS)-induced soluble TNF-α production in mice in a dose-dependent manner. At an oral dose of 200mg/kg, marimastat almost completely inhibited LPS-induced soluble TNF-α production, but only slightly delayed LPS lethality. On the other hand, anti-TNF-α antibodies completely abolished LPS-induced morbidity. In addition, anti-TNF-α antibodies, but not marimastat (200mg/kg/day), inhibited the development of arthritis in human TNF-α transgenic mice. These results suggest that cell surface TNF-α may be important in the pathogenesis of murine models for sepsis and arthritis.