Low endogenous prostaglandin E2 predisposes to relapsing inflammation in experimental rat enterocolitis

Intramural injection of peptidoglycan-polysaccharide (PG-PS) induces acute enterocolitis that spontaneously relapses in Lewis but not Fischer rats. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) induce prostaglandin E-2 (PGE(2)) secretion, which inhibits secretion of these cytokines by macrophages, suggesting an inhibitory feedback mechanism. We postulate that Lewis rat susceptibility to relapse is due to an imbalance between protective prostaglandins and cytokines. Female Fischer and Lewis rats were injected with PG-PS (37.5 mug/g) or human serum albumin intramurally. Tissue IL-1 alpha and PGE(2) immunoreactivities and myeloperoxidase (MPO) activity were determined. Relapsing rats had lower PGE(2) and PGE(2)/IL-1 alpha ratios than nonrelapsing rats (P < 0.05). In Fischer rats, 2 mg/kg/day of indomethacin potentiated cecal MPO and IL-1<alpha> concentrations above PG-PS alone (P < 0.05), Misoprostol treatment blocked PG-PS induced IL-la and MPO and inhibited the potentiating effect of indomethacin on MPO and IL-1<alpha> (P < 0.05). In conclusion, increased endogenous PG may be protective against relapsing inflammation in PG-PS induced enterocolitis, at least. partially via inhibition of proinflammatory cytokines. Imbalance between protective prostaglandins and proinflammatory cytokines may be involved in the pathogenesis of chronic relapsing inflammation in genetically susceptible hosts.