Indomethacin induces the suppression of plasma neutral proteinase activity in mice: possible relationship to efficacy as an anti-inflammatory drug and induction of alterations in the immune system.

Treatment of BALB/c, C57Bl/6 or C3H/HeJ mice with non-toxic concentrations of indomethacin (75-100 micrograms/day) led to a depression of plasma neutral proteinase activity as determined with an (125I)-caseinolytic assay. Lower concentrations of indomethacin (50 micrograms/day), aspirin (1 mg/day), LiCl (3 meq/kg/day), Sulindac (100 micrograms/day), indomethacin analogs (MK-410, MK-555) or lipopolysaccharide (100 micrograms) did not induce depression in proteinase activity. Indomethacin did not directly inhibit the proteinase activity of normal plasma in vitro. The in vivo effects of indomethacin were reversible and plasma proteinase activity returned to normal values within 8 days of cessation of treatment. These results indicate that indomethacin can uniquely alter plasma proteinase homeostasis in normal mice. While effective in depressing the plasma proteinase activity of normal mice, treatment of mice bearing either the BCL1 leukemia or the B16-F10 melanoma with indomethacin did not depress the elevated plasma proteinase levels detected in tumor-bearing animals. Thus the elevation in proteinases detected in tumor-bearing animals may not be the result of increased prostaglandin synthesis and plasma proteinase activity in such disease states may be regulated differently than in normal mice. However, the ability of this potent anti-inflammatory agent to alter proteinase metabolism may contribute to its therapeutic efficacy in the management of inflammatory disease.