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

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