title: Prostaglandin E2 augments IL-10 signaling and function.
abstract: In inflamed joints of rheumatoid arthritis, PGE(2) is highly expressed, and IL-10 and IL-6 are also abundant. PGE(2) is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE(2) on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE(2) significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE(2) suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE(2)-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE(2)-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE(2) selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE(2) may modulate immune responses by alteration of cytokine signaling in THP-1 cells.
authors.affiliation: Department of Pathology, College of Medicine, Korea University, 126-1, Anam-Dong 5-Ga, Sungbuk-Gu, Seoul 136-705, Korea.
authors.forename: Hyeonjoo
authors.initials: H
authors.lastname: Cheon
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Rho
authors.forename: Seong Jae
authors.initials: SJ
authors.lastname: Choi
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Gwan Gyu
authors.initials: GG
authors.lastname: Song
authors.forename: Jeongwon
authors.initials: J
authors.lastname: Sohn
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Won
authors.forename: Jong Dae
authors.initials: JD
authors.lastname: Ji
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D018121:Receptors, Cytokine / Q000096:biosynthesis; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; D018121:Receptors, Cytokine; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone