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

Published on May 1, 2017in Journal of Immunology4.718
· DOI :10.4049/jimmunol.1602072
Zbigniew Zasłona9
Estimated H-index: 9
(Trinity College, Dublin),
Eva M. Palsson-McDermott23
Estimated H-index: 23
(Trinity College, Dublin)
+ 6 AuthorsLuke A. J. O'Neill109
Estimated H-index: 109
(Trinity College, Dublin)
PGE 2 has been shown to increase the transcription of pro–IL-1β. However, recently it has been demonstrated that PGE 2 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 2 on IL-1β production. We have found that in murine bone marrow–derived macrophages, PGE 2 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 2 on IL-1β production. By blocking PGE 2 production with indomethacin, we made a striking finding that endogenous PGE 2 is essential for LPS-induced pro–IL-1β 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-1β, PGE 2 boosted LPS-induced IL-1β production. PGE 2 did not inhibit ATP-induced mature IL-1β production in monocytes. Because PGE 2 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 2 , 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 2 on TNF-α production.
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