title: The Induction of Pro-IL-1β by Lipopolysaccharide Requires Endogenous Prostaglandin E2Production.
abstract: PGE2has been shown to increase the transcription of pro-IL-1β. However, recently it has been demonstrated that PGE2can 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 PGE2on IL-1β production. We have found that in murine bone marrow-derived macrophages, PGE2via 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 PGE2on IL-1β production. By blocking PGE2production with indomethacin, we made a striking finding that endogenous PGE2is essential for LPS-induced pro-IL-1β production, suggesting a positive feedback loop. The effect of endogenous PGE2was mediated by EP2 receptor. In primary human monocytes, where LPS alone is sufficient to induce mature IL-1β, PGE2boosted LPS-induced IL-1β production. PGE2did not inhibit ATP-induced mature IL-1β production in monocytes. Because PGE2mediates 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 PGE2on TNF-α production.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Zasłona
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Pålsson-McDermott
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Menon
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Moritz
authors.identifier: 0000-0003-1529-9677
authors.initials: M
authors.lastname: Haneklaus
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Flis
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Hannah
authors.initials: H
authors.lastname: Prendeville
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Corcoran
authors.affiliation: Division of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Marc
authors.identifier: 0000-0002-9768-0262
authors.initials: M
authors.lastname: Peters-Golden
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and laoneill@tcd.ie.
authors.forename: Luke A J
authors.initials: LAJ
authors.lastname: O'Neill
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025461:Feedback, Physiological; D005334:Fever / Q000276:immunology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D015232:Dinoprostone; D007213:Indomethacin