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

被引：38

作者：

Kuo, Chang-Hung ^{[1
,2
,3
]}

Ko, Ying-Chin ^{[4
,7
,8
]}

Yang, San-Nan ^{[1
,3
,6
,8
]}

Chu, Yu-Te ^{[1
]}

Wang, Wei-Li ^{[1
,2
]}

Huang, Shau-Ku ^{[5
]}

Chen, Huan-Nan ^{[1
]}

Wei, Wan-Ju ^{[1
]}

Jong, Yuh-Jyh ^{[1
,3
,6
,8
]}

Hung, Chih-Hsing ^{[1
,2
,3
,6
,8
]}

机构：

[1] Kaohsiung Med Univ, Dept Pediat, Kaohsiung Med Univ Hosp, Kaohsiung 807, Taiwan

[2] Kaohsiung Municipal Tatung Hosp, Dept Pediat, Kaohsiung, Taiwan

[3] Kaohsiung Med Univ, Grad Inst Med, Coll Med, Kaohsiung 807, Taiwan

[4] Kaohsiung Med Univ, Dept Publ Hlth & Environm Med, Fac Med, Coll Med, Kaohsiung 807, Taiwan

[5] Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD 21224 USA

[6] Kaohsiung Med Univ, Dept Pediat, Fac Med, Coll Med, Kaohsiung 807, Taiwan

[7] Natl Hlth Res Inst, Div Environm Hlth & Occupat Med, Kaohsiung, Taiwan

[8] Kaohsiung Med Univ, Ctr Excellence Environm Med, Kaohsiung 807, Taiwan

来源：

JOURNAL OF MOLECULAR MEDICINE-JMM | 2011年 / 89卷 / 01期

关键词：

Prostaglandin I-2; Epigenetics; Interferon-gamma-inducible protein-10; Macrophage-derived chemokine; Monocytes; GENE-EXPRESSION; PROSTACYCLIN ANALOGS; DENDRITIC CELLS; MOUSE MODEL; ASTHMA; INFLAMMATION; TRANSCRIPTION; PROTEIN-10; RESPONSES; CHROMATIN;

D O I：

10.1007/s00109-010-0694-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：29 / 41

页数：13

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