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Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation

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Abstract

Chemokines play important roles in asthma. Prostaglandin I2 (PGI2) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI2 analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI2 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. PGI2 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). PGI2 analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI2 analogue-enhanced MDC expression was reduced by nuclear factor (NF) κB inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI2 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. PGI2 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. PGI2 analogues may therefore increase Th2 recruitment and inflammation.

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Acknowledgements

The project is supported by a grant from the Center of Excellence for Environmental Medicine Kaohsiung Medical University Research Foundation KMU-EM-98-4.1and 98-4.2, and Kaohsiung Medical University Hospital Research Foundation KMUH99-9I08.

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Authors and Affiliations

  1. Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, Republic of China

    Chang-Hung Kuo, Wei-Li Wang & Chih-Hsing Hung

  2. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No.100, Tz-You 1st Road, Kaohsiung, 807, Taiwan, Republic of China

    Chang-Hung Kuo, San-Nan Yang, Yu-Te Chu, Wei-Li Wang, Huan-Nan Chen, Wan-Ju Wei, Yuh-Jyh Jong & Chih-Hsing Hung

  3. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Chang-Hung Kuo, San-Nan Yang, Yuh-Jyh Jong & Chih-Hsing Hung

  4. Department of Public Health and Environmental Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Ying-Chin Ko

  5. Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Ying-Chin Ko, San-Nan Yang, Yuh-Jyh Jong & Chih-Hsing Hung

  6. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Kaohsiung, Taiwan, Republic of China

    Ying-Chin Ko

  7. Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    San-Nan Yang, Yuh-Jyh Jong & Chih-Hsing Hung

  8. Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA

    Shau-Ku Huang

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  1. Chang-Hung Kuo
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Correspondence to Chih-Hsing Hung.

Additional information

Yuh-Jyh Jong and Chih-Hsing Hung contributed equally to this manuscript

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Kuo, CH., Ko, YC., Yang, SN. et al. Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation. J Mol Med 89, 29–41 (2011). https://doi.org/10.1007/s00109-010-0694-2

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  • DOI: https://doi.org/10.1007/s00109-010-0694-2

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