Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation
| Autor: | San Nan Yang, Chih Hsing Hung, Ming-Yii Huang, Ya Ling Hsu, Yi Pin Chen, Shau Ku Huang, Wan Ju Wei, Hsiu-Lin Chen, Ching Hsiung Lin, Yuh-Jyh Jong, Chang Hung Kuo, Po-Lin Kuo |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
T-Lymphocytes medicine.medical_treatment Prostaglandin E2 receptor Receptors Prostaglandin Receptors Epoprostenol Methylation Epigenesis Genetic Histones chemistry.chemical_compound Interferon Internal medicine Cyclic AMP Genetics medicine Humans Receptors Prostaglandin E PPAR alpha Iloprost Molecular Biology Cells Cultured Genetics (clinical) Forskolin Activating Transcription Factor 2 biology Articles Dendritic Cells Epoprostenol Molecular biology Activating transcription factor 2 PPAR gamma Cytokine Endocrinology chemistry biology.protein Cytokines Molecular Medicine Calcium lipids (amino acids peptides and proteins) Tumor necrosis factor alpha Mitogen-Activated Protein Kinases Chromatin immunoprecipitation medicine.drug |
| Zdroj: | Molecular Medicine. 18:433-444 |
| ISSN: | 1528-3658 1076-1551 |
| DOI: | 10.2119/molmed.2011.00193 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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