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  • Title: Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastropathy.
    Author: Wallace JL, Keenan CM, Cucala M, Mugridge KG, Parente L.
    Journal: Gastroenterology; 1992 Apr; 102(4 Pt 1):1176-85. PubMed ID: 1348040.
    Abstract:
    Interleukin 1 (IL-1) has been shown to reduce the severity of experimental gastroduodenal ulceration, but the mechanism of action is unclear. The present study examined the possibility that the mechanism underlying the protective effects of IL-1 in experimental nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is related to effects on gastric acid secretion, on prostaglandin synthesis, and/or on neutrophil function. IL-1 alpha and IL-1 beta dose-dependently (1-10 micrograms/kg) reduced the severity of gastric damage induced by indomethacin, whereas tumor necrosis factor alpha (1-10 micrograms/kg) had no effect. These effects of IL-1 were not completely attributable to a reduction in the volume or acidity of gastric secretion during the 1-hour pretreatment period. Whereas IL-1 alpha and IL-1 beta significantly inhibited pentagastrin-stimulated acid secretion, the dose-response relationship and time course of actions suggested that effects on acid secretion did not fully account for the ability of these agents to reduce indomethacin-induced gastric injury. The maximally effective dose of IL-1 beta (10 micrograms/kg) in terms of reduction of indomethacin-induced gastric injury did not significantly affect gastric prostaglandin synthesis. Neutrophil function was assessed using two in vivo assays. IL-1 beta inhibited migration of neutrophils in response to intradermal injections of N-formyl-methionyl-leucyl-phenylalanine and leukotriene B4 (LTB4) and dose-dependently (0.1-10 micrograms/kg) inhibited LTB4-induced neutropenia. These effects could be mimicked by dexamethasone (1 mg/kg SC), which inhibited the neutropenic response to LTB4 and significantly (P less than 0.001) reduced the severity of indomethacin-induced gastric damage. Both IL-1 beta and dexamethasone could significantly reduce the extent of histologically detectable leukocyte margination within the gastric mucosal microcirculation after indomethacin administration. The results of this study suggest that effects of IL-1 on gastric acid secretion or prostaglandin synthesis do not fully account for its ability to reduce the severity of experimental NSAID-induced gastropathy, whereas inhibitory effects of IL-1 on neutrophil function may contribute significantly to its protective actions.
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