title: Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation.
abstract: Chemokines play important roles in asthma. Prostaglandin I(2) (PGI(2)) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI(2) analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI(2) analogues on the expression of Th1-related chemokine interferon-γ-inducible protein-10 (IP-10/CXCL10) and Th2-related chemokine macrophage-derived chemokine (MDC/CCL22) in human monocytes. The human monocytes were pretreated with iloprost and treprostinil before lipopolysaccharide (LPS) stimulation. IP-10 and MDC were measured by ELISA. Intracellular signaling was investigated by cyclic adenosine monophosphate (cAMP) assay, western blot and chromatin immunoprecipitation. PGI(2) analogues enhanced MDC, but suppressed IP-10 expression in LPS-stimulated monocytes. These effects were reversed by the I prostanoid (IP) receptor antagonist (CAY10449), peroxisomal proliferators-activated receptor (PPAR)-α antagonist (GW6741) and PPAR-γ antagonist (GW9662). PGI(2) analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI(2) analogue-enhanced MDC expression was reduced by nuclear factor (NF) κB inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI(2) analogues up-regulated phospho-p65 and phospho-p38 but down-regulated phospho-ERK expression. Iloprost enhanced H3 acetylation in MDC promoter area and suppressed H3 acetylation, H3K4, and H3K36 trimethylation in IP-10 promoter area. PGI(2) analogues enhanced MDC expression via the I prostanoid-receptor-cAMP, PPAR-α and PPAR-γ, NFκB-p65, MAPK-p38-ATF2 pathways and increasing histone acetylation, and suppressed IP-10 expression via the IP-receptor-cAMP, PPAR-γ, MAPK-ERK-ELK1 pathways and inhibiting histone acetylation and trimethylation in LPS-stimulated monocytes. PGI(2) analogues may therefore increase Th2 recruitment and inflammation.
authors.affiliation: Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, Republic of China.
authors.forename: Chang-Hung
authors.initials: CH
authors.lastname: Kuo
authors.forename: Ying-Chin
authors.initials: YC
authors.lastname: Ko
authors.forename: San-Nan
authors.initials: SN
authors.lastname: Yang
authors.forename: Yu-Te
authors.initials: YT
authors.lastname: Chu
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Wang
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
authors.forename: Huan-Nan
authors.initials: HN
authors.lastname: Chen
authors.forename: Wan-Ju
authors.initials: WJ
authors.lastname: Wei
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
authors.forename: Chih-Hsing
authors.initials: CH
authors.lastname: Hung
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology*; D000242:Cyclic AMP / Q000276:immunology; D057890:Epigenomics; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D018927:Anti-Asthmatic Agents; D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011464:Epoprostenol; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D016285:Iloprost; C427248:treprostinil