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

Chang Hung Kuo, Ying Chin Ko, San Nan Yang, Yu Te Chu, Wei Li Wang, Shau Ku Huang, Huan Nan Chen, Wan Ju Wei, Yuh Jyh Jong, Chih Hsing Hung

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)29-41
Number of pages13
JournalJournal of Molecular Medicine
Volume89
Issue number1
DOIs
StatePublished - Jan 1 2011

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Keywords

  • Epigenetics
  • Interferon-γ-inducible protein-10
  • Macrophage-derived chemokine
  • Monocytes
  • Prostaglandin I

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Kuo, C. H., Ko, Y. C., Yang, S. N., Chu, Y. T., Wang, W. L., Huang, S. K., Chen, H. N., Wei, W. J., Jong, Y. J., & Hung, C. H. (2011). Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation. Journal of Molecular Medicine, 89(1), 29-41. https://doi.org/10.1007/s00109-010-0694-2