TNFα processing enzyme inhibitors prevent aspirin‐induced TNFα release and protect against gastric mucosal injury in rats

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Abstract
Background: Although previous studies indicate that prevention of tumour necrosis factor α (TNFα) release protects against NSAID‐induced gastric mucosal injury, intracellular pathways by which aspirin causes TNFα release are unknown. TNFα is synthesized as a precursor which is proteolytically cleaved by a specific converting enzyme, TACE, to release the mature cytokine. TACE inhibitors prevent TNFα release and protect against TNFα‐mediated disease.Aim: To investigate: (i) molecular events that regulate TNFα secretion in response to aspirin in vivo and in vitro; (ii) whether TNFα secretion inhibitors prevent aspirin‐induced TNFα release and protect against gastric mucosal damage; and (iii) whether TNFα exerts a direct cytotoxic effect on gastric epithelial cells.Methods: In vitro studies were carried out on mouse macrophages and rat gastric mucosal cells. Gastric mucosal damage was induced in rats by oral administration of 300 mg/kg aspirin. TNFα cytotoxicity on gastric mucosal cells was examined by treating rats with lipopolysaccharide to release TNFα or by incubating dispersed gastric mucosal cells with increasing concentrations of TNFα.Results: Aspirin increases intracellular calcium (Ca2+) levels and causes a time and concentration dependent increase in macrophage TNFα mRNA accumulation and cytokine release. Agents that cause Ca2+ mobilization with a receptor‐independent mechanism, such as ionomycin and thapsigargin, stimulate TNFα release. Incubating the macrophages in a Ca2+ free medium inhibited TNFα secretion. Agents that prevent TNFα mRNA transcription, e.g. lisophylline, PGE2, interleukin‐10 and 8‐BrcAMP, or TACE inhibitors, e.g. EDTA, TAPI‐2 and BB‐3103, inhibit TNFα release and protect rats against gastric mucosal injury induced by oral administration of aspirin. TNFα exerts a direct␣cytotoxic effect on gastric epithelial cells as demonstrated by the reduced viability observed in gastric mucosal␣cells prepared from rats treated with lipopolysaccharide, or␣directly incubated with increasing concentrations of TNFα.Conclusions: (i) Aspirin directly stimulates TNFα gene transcription; (ii) TACE inhibitors protect against aspirin‐induced gastric mucosal injury; and (iii) TNFα exerts a direct cytotoxic effect on gastric epithelial cells.