Effects of PGI2 analogues on Th1-and Th2-related chemokines in monocytes via epigenetic regulation
Effects of PGI2 analogues on Th1-and Th2-related chemokines in monocytes via epigenetic regulation
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DOI：
10.1007/s00109-010-0694-2
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发表时间：
2011-01-01
影响因子：
4.7
通讯作者：
Hung, Chih-Hsing
中科院分区：
文献类型：
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作者：
Kuo, Chang-Hung;Ko, Ying-Chin;Hung, Chih-Hsing
趋化因子在哮喘中起重要作用。前列腺素I-2(PGI(2))类似物最近被认为是治疗哮喘的候选药物。然而，PGI(2)类似物对Th1和Th2相关趋化因子表达的影响尚不清楚。为此，我们研究了PGI(2)类似物对人单核细胞Th1相关趋化因子干扰素-γ诱导蛋白10(IP-10/CXCL10)和Th2相关趋化因子巨噬细胞衍生趋化因子(MDC/CCL22)表达的影响。人单核细胞在内毒素(LPS)刺激前用伊洛前列素和曲普替尼进行预处理。用双抗体夹心法测定IP-10和MDC。用环磷酸腺苷(CAMP)法、免疫印迹和染色质免疫沉淀法检测细胞内信号转导。PGI(2)类似物可促进内毒素刺激的单核细胞表达MDC，但抑制IP-10的表达。I-前列腺素(IP)受体拮抗剂(CAY10449)、PPAR-α拮抗剂(GW6741)和PPAR-γ拮抗剂(GW9662)可逆转上述作用。PGI(2)类似物可增加细胞内cAMP水平。腺苷环化酶激活剂Forsklin也有类似的作用。核因子kappaB抑制剂(BAY 117085)和丝裂原活化蛋白激酶-p38抑制剂(SB203580)可抑制PGI(2)类似物增强的mDC的表达。PGI(2)类似物上调磷酸化p65和磷酸化p38，但下调磷酸化ERK的表达。伊洛前列素促进MDC启动子区域的H3乙酰化，抑制IP-10启动子区域的H3乙酰化、H3K4和H3K36三甲基化。PGI(2)类似物通过I-前列腺素受体-cAMP、PPAR-α和PPAR-γ、NF-kappa B-p65、MAPK-p38-ATF2途径和增强组蛋白乙酰化途径促进MDC的表达，通过IP受体-cAMP、PPAR-γ、MAPK-ERK-ELK1途径抑制IP-10的表达，抑制组蛋白乙酰化和三甲基化。因此，PGI(2)类似物可能会增加Th2的募集和炎症。
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.