The Induction of Pro-IL-1β by Lipopolysaccharide Requires Endogenous Prostaglandin E2 Production

PGE(2) has been shown to increase the transcription of pro IL-1 beta. However, recently it has been demonstrated that PGE(2) can block the maturation of IL-1 beta by inhibiting the NLRP3 inflammasome in macrophages. These apparently conflicting results have led us to reexamine the effect of PGE(2) on IL-1 beta production. We have found that in murine bone marrow derived macrophages, PGE(2) via the cAMP/protein kinase A pathway is potently inducing IL-1 beta transcription, as well as boosting the ability of LPS to induce IL-1 beta mRNA and pro IL-1 beta while inhibiting the production of TNF-alpha. This results in an increase in mature IL-1 beta production in macrophages treated with ATP. We also examined the effect of endogenously produced PGE(2) on IL-1 beta production. By blocking PGE(2) production with indomethacin, we made a striking fmding that endogenous PGE(2) is essential for LPS-induced pro-IL-1 beta production, suggesting a positive feedback loop. The effect of endogenous PGE(2) was mediated by EP2 receptor. In primary human monocytes, where LPS alone is sufficient to induce mature IL-1 beta, PGE(2) boosted LPS-induced IL-1 beta production. PGE(2) did not inhibit ATP-induced mature IL-1 beta production in monocytes. Because PGE(2) mediates the pyrogenic effect of IL-1 beta, these effects might be especially relevant for the role of monocytes in the induction of fever. A positive feedback loop from IL-1 beta and back to PGE(2), which itself is induced by IL-1 beta, is likely to be operating. Furthermore, fever might therefore occur in the absence of a septic shock response because of the inhibiting effect of PGE(2) on TNF-alpha production.