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

Abstract

PGE₂ has been shown to increase the transcription of pro-IL-1β. However, recently it has been demonstrated that PGE₂ 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 PGE₂ on IL-1β production. We have found that in murine bone marrow-derived macrophages, PGE₂ 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 PGE₂ on IL-1β production. By blocking PGE₂ production with indomethacin, we made a striking finding that endogenous PGE₂ is essential for LPS-induced pro-IL-1β production, suggesting a positive feedback loop. The effect of endogenous PGE₂ was mediated by EP2 receptor. In primary human monocytes, where LPS alone is sufficient to induce mature IL-1β, PGE₂ boosted LPS-induced IL-1β production. PGE₂ did not inhibit ATP-induced mature IL-1β production in monocytes. Because PGE₂ 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 PGE₂, 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 PGE₂ on TNF-α production.