Effect of prostaglandin I2 analogs on cytokine expression in human myeloid dendritic cells via epigenetic regulation.
Prostaglandin I(2) (PGI(2)) analog is regarded as a potential candidate for treating asthma. Human myeloid dendritic cells (mDCs) play a critical role in the pathogenesis of asthma. However, the effects of PGI(2) analog on human mDCs are unknown. In the present study, circulating mDCs were isolated from six healthy subjects. The effects of PGI(2) analogs iloprost and treprostinil on cytokine production, maturation and T-cell stimulatory function of human mDCs were investigated. Tumor necrosis factor (TNF)-α and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay. The expression of costimulatory molecules was investigated by flow cytometry. T-cell stimulatory function was investigated by measuring interferon (IFN)-γ, IL-13 and IL-10 production by T cells cocultured with iloprost-treated mDCs. Intracellular signaling was investigated by Western blot and chromatin immunoprecipitation. We found that iloprost and treprostinil induced IL-10, but suppressed TNF-α production in polyinosinic-polycytidylic acid (poly I:C)-stimulated mDCs. This effect was reversed by the I-prostanoid (IP), E-prostanoid (EP) receptor antagonists or intracellular free calcium (Ca(2+)) chelator. Forskolin, an adenyl cyclase activator, conferred a similar effect. Iloprost and treprostinil increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, and iloprost also increased intracellular Ca(2+). Iloprost suppressed poly I:C-induced mitogen-activated protein kinase (MAPK) phospho-p38 and phospho-activating transcription factor (ATF)2 expression. Iloprost downregulated poly I:C-induced histone H3K4 trimethylation in the TNFA gene promoter region via suppressing translocation of histone 3 lysine 4 (H3K4)-specific methyltransferases MLL (mixed lineage leukemia) and WDR5 (WD repeat domain 5). Iloprost-treated mDCs inhibited IL-13, IFN-γ and IL-10 production by T cells. In conclusion, PGI(2) analogs enhance IL-10 and suppress TNF-α expression through the IP/EP2/EP4 receptors-cAMP and EP1 receptor-Ca(2+) pathway. Iloprost suppressed TNF-α expression via the MAPK-p38-ATF2 pathway and epigenetic regulation by downregulation of histone H3K4 trimethylation.
Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chang-Hung
CH
Kuo
Ching-Hsiung
CH
Lin
San-Nan
SN
Yang
Ming-Yii
MY
Huang
Hsiu-Lin
HL
Chen
Po-Lin
PL
Kuo
Ya-Ling
YL
Hsu
Shau-Ku
SK
Huang
Yuh-Jyh
YJ
Jong
Wan-Ju
WJ
Wei
Yi-Pin
YP
Chen
Chih-Hsing
CH
Hung
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D044127:Epigenesis, Genetic; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D008745:Methylation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D016207:Cytokines; D006657:Histones; D047493:PPAR alpha; D047495:PPAR gamma; C113936:PTGIR protein, human; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D011464:Epoprostenol; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D016285:Iloprost; C427248:treprostinil; D002118:Calcium