Effects of PGI sub(2) analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2011-01, Vol.89 (1), p.29-41
• Main Authors: Kuo, Chang-Hung, Ko, Ying-Chin, Yang, San-Nan, Chu, Yu-Te, Wang, Wei-Li, Huang, Shau-Ku, Chen, Huan-Nan, Wei, Wan-Ju, Jong, Yuh-Jyh, Hung, Chih-Hsing
• Format: Article
• Language: English
• Subjects: Acetylation
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-010-0694-2

Chemokines play important roles in asthma. Prostaglandin I sub(2) (PGI sub(2)) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI sub(2) analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI sub(2) analogues on the expression of Th1-related chemokine interferon- gamma -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. PGI sub(2) 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)- alpha antagonist (GW6741) and PPAR- gamma antagonist (GW9662). PGI sub(2) analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI sub(2) analogue-enhanced MDC expression was reduced by nuclear factor (NF) Kappa B inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI sub(2) 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. PGI sub(2) analogues enhanced MDC expression via the I prostanoid-receptor-cAMP, PPAR- alpha and PPAR- gamma , NF Kappa B-p65, MAPK-p38-ATF2 pathways and increasing histone acetylation, and suppressed IP-10 expression via the IP-receptor-cAMP, PPAR- gamma , MAPK-ERK-ELK1 pathways and inhibiting histone acetylation and trimethylation in LPS-stimulated monocytes. PGI sub(2) analogues may therefore increase Th2 recruitment and inflammation.