Regulation of macrophage tumor necrosis factor production by prostaglandin E2

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Abstract

We have studied the role of prostaglandin E2 on the modulation of tumor necrosis factor by immunologically elicited and lipopolysaccharide treated murine macrophages. Indomethacin, a potent inhibitor of prostaglandin E2 production, caused a dose dependent augmentation of lipopolysaccharide induced tumor necrosis factor production (2–3 fold at 10−7 molar). Tumor necrosis factor was released into the extracellular environment and no activity was found to be associated with membrane or cytosolic fractions. Prostaglandin E2 added to the lipopolysaccharide treated cultures suppressed tumor necrosis factor in a dose dependent manner. In these studies, 10−7 molar PGE2 reduced tumor necrosis factor production to basal levels. These data suggest that PGE2 may be a potent autoregulatory factor that dramatically influences tumor necrosis factor production.

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    Citation Excerpt :

    The important experimental observations that NSAIDs, by reducing levels of PGs, were able to increase or augment the expression and release of TNF from macrophages and other cells65,68,76,77 and PG supplementation was highly efficacious in the management of NSAIDs enteropathy39,78 have opened new paradigms to the role of TNF in NSAID enteropathy. Today, there is enough experimental evidence which suggests that the ability of macrophages to release TNF is regulated by PGs.69,76,79 In particular, PGE2 has been reported to be a potent inhibitor of TNF release and gene expression in macrophages.68,69 Normally, PGs and in particular the intestinal PGE2 inhibit TNF biosynthesis in a feedback loop80,81 and conversely, inhibition of PG synthesis by NSAIDs may increase TNF production.67,82,83

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