| Effect of PGI(2) Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation. | |
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MedLine Citation:
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PMID: 22231731 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 myeloid DCs (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 ELISA. The expression of costimulatory molecules were 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 immunoprecepitation. 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 cAMP levels, and iloprost also increased intracellular Ca(2+). Iloprost suppressed poly I:C-induced mitogen-activated protein kinase (MAPK) phospho-p38 and phospho-ATF2 expression. Iloprost down-regulated poly I:C-induced histone H3K4 trimethylation in the TNFA gene promoter region via suppressing translocation of H3K4 specific methyltransferases, MLL and WDR5. 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 down-regulation of histone H3K4 trimethylation. |
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Authors:
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Chang-Hung Kuo; Ching-Hsiung Lin; San-Nan Yang; Ming-Yii Huang; Hsiu-Lin Chen; Po-Lin Kuo; Ya-Ling Hsu; Shau-Ku Huang; Yuh-Jyh Jong; Wan-Ju Wei; Yi-Pin Chen; Chih-Hsing Hung |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-07 |
Journal Detail:
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Title: Molecular medicine (Cambridge, Mass.) Volume: - ISSN: 1528-3658 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2012-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9501023 Medline TA: Mol Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. |
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