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Alkaline protease purified from Aspergillus oryzae prevents TNF‐a‐induced acute inflammation in the mouse small intestine

Enzyme replacement therapy is a growing clinical intervention primarily directed at correcting enzyme deficiencies, including the impaired production of digestive enzymes. We have asked whether microbial proteases have any potential therapeutic value in the treatment of inflammatory conditions whose pathogenesis involves peptide inflammatory mediators. The proteases of Aspergillus oryzae were selected due to their routine use in the processing foods. Pretreating mice with a partially purified mixture of A. oryzae proteases protected them against TNF‐α‐dependent lethality in an endotoxemia model. Pretreated mice showed decreased concentrations of detectable TNF‐α, following challenge with bacterial endotoxin. Treating TNF‐ α with this protease preparation partially degraded the cytokine and blocked its ability to induce nitric oxide production by mouse myoblast cells in vitro. Three proteases were purified from this preparation by ion exchange chromatography and found by amino‐terminal sequencing to be alkaline protease (AP), deuterolysin (DE) and 26 kDa protease. Purified AP inactivated mouse TNF‐α. Treating TNF‐ α in vitro with AP, also destroyed its ability to induce activated caspase‐3 in intestinal epithelial cells in vivo. Injecting with 1 μg AP by the i.p. route as much as 15 min prior to challenge with 5 ng TNF‐α blocked the activation of intestinal caspase‐3. These results suggest that A. oryzae AP has anti‐inflammatory activity that may have therapeutic value in treating TNF‐α‐dependent inflammatory bowel diseases.