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Molecular Medicine

, Volume 18, Issue 3, pp 433–444 | Cite as

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

  • 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
Research Article

Abstract

Prostaglandin I2 (PGI2) 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 PGI2 analog on human mDCs are unknown. In the present study, circulating mDCs were isolated from six healthy subjects. The effects of PGI2 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 (Ca2+) 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 Ca2+. 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, PGI2 analogs enhance IL-10 and suppress TNF-α expression through the IP/EP2/EP4 receptors-cAMP and EP1 receptor-Ca2+ pathway. Iloprost suppressed TNF-α expression via the MAPK-p38-ATF2 pathway and epigenetic regulation by downregulation of histone H3K4 trimethylation.

Notes

Acknowledgments

This study was supported by a grant from the Center of Excellence Environmental Medicine Kaohsiung Medical University Research Foundation (KMU-EM-98-4), the National Science Council (NSC 99-2314-B-37-014-MY3) and the Kaohsiung Medical University Hospital (KMUH-96-6G23, KMUH-97-7G51, KMUH-98-8G09 and KMUH99-9I08).

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Authors and Affiliations

  • Chang-Hung Kuo
    • 1
    • 2
    • 3
  • Ching-Hsiung Lin
    • 4
    • 5
    • 6
  • San-Nan Yang
    • 1
    • 3
    • 7
  • Ming-Yii Huang
    • 8
    • 9
  • Hsiu-Lin Chen
    • 1
    • 10
  • Po-Lin Kuo
    • 11
  • Ya-Ling Hsu
    • 3
  • Shau-Ku Huang
    • 3
    • 12
    • 13
  • Yuh-Jyh Jong
    • 1
    • 3
    • 6
    • 12
  • Wan-Ju Wei
    • 1
  • Yi-Pin Chen
    • 1
  • Chih-Hsing Hung
    • 1
    • 2
    • 3
    • 7
    • 12
  1. 1.Department of Pediatrics, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan, Republic of China
  2. 2.Department of PediatricsKaohsiung Municipal Ta-Tung HospitalKaohsiungTaiwan
  3. 3.Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.Division of Chest Medicine, Department of Internal MedicineChanghua Christian HospitalChanghuaTaiwan
  5. 5.School of MedicineChung Shan Medical UniversityTaichungTaiwan
  6. 6.Department of Respiratory Care, College of Health SciencesChang Jung Christian UniversityTainanTaiwan
  7. 7.Department of Pediatrics, School of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  8. 8.Department of Radiation OncologyKaohsiung Medical University HospitalKaohsiungTaiwan
  9. 9.Department of Radiation Oncology, School of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  10. 10.Department of Respiratory Therapy, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  11. 11.Graduate Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  12. 12.Center of Excellence for Environmental MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  13. 13.Johns Hopkins Asthma and Allergy Center, School of MedicineJohns Hopkins UniversityBaltimoreUSA

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