期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 89, 期 1, 页码 29-41出版社
SPRINGER
DOI: 10.1007/s00109-010-0694-2
关键词
Prostaglandin I-2; Epigenetics; Interferon-gamma-inducible protein-10; Macrophage-derived chemokine; Monocytes
资金
- Center of Excellence for Environmental Medicine Kaohsiung Medical University Research Foundation [KMU-EM-98-4.1, 98-4.2]
- Kaohsiung Medical University Hospital Research Foundation [KMUH99-9I08]
Chemokines play important roles in asthma. Prostaglandin I-2 (PGI(2)) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI(2) analogues on the expression of Th1- and Th2-related chemokincs are unknown. To this end, we investigated the in vitro effects of PGI(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(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(2) analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI(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(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(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(2) analogues may therefore increase Th2 recruitment and inflammation.
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