Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, Republic of China.
J Mol Med (Berl). 2011 Jan;89(1):29-41. doi: 10.1007/s00109-010-0694-2. Epub 2010 Nov 18.
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 chemokines are unknown. To this end, we investigated the in vitro effects of PGI(2) 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. 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)-α antagonist (GW6741) and PPAR-γ 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) κB 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-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. PGI(2) analogues may therefore increase Th2 recruitment and inflammation.
趋化因子在哮喘中发挥重要作用。前列腺素 I（2）（PGI（2））类似物最近被提议作为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）类似物在脂多糖（LPS）刺激下人单核细胞中 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）表达的体外效应。在 LPS 刺激前，用伊洛前列素和曲前列素预处理人单核细胞。通过 ELISA 测定 IP-10 和 MDC。通过环磷酸腺苷（cAMP）测定、western blot 和染色质免疫沉淀研究细胞内信号。PGI（2）类似物增强 LPS 刺激的单核细胞中 MDC，但抑制 IP-10 的表达。这些作用被 I 前列腺素（IP）受体拮抗剂（CAY10449）、过氧化物酶体增殖物激活受体（PPAR）-α拮抗剂（GW6741）和 PPAR-γ拮抗剂（GW9662）逆转。PGI（2）类似物增加细胞内 cAMP 水平。腺苷酸环化酶激活剂 Forskolin 具有类似的作用。PGI（2）类似物增强的 MDC 表达被核因子（NF）κB 抑制剂（BAY 117085）和丝裂原激活蛋白激酶（MAPK）-p38 抑制剂（SB203580）减少。PGI（2）类似物上调磷酸化 p65 和磷酸化 p38，但下调磷酸化 ERK 表达。伊洛前列素增强 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 IP 前列腺素受体-cAMP、PPAR-α和 PPAR-γ、NFκB-p65、MAPK-p38-ATF2 途径增强 MDC 表达，增加组蛋白乙酰化，并通过 IP 受体-cAMP、PPAR-γ、MAPK-ERK-ELK1 途径抑制 IP-10 表达，并抑制 LPS 刺激的单核细胞中的组蛋白乙酰化和三甲基化。因此，PGI（2）类似物可能增加 Th2 募集和炎症。
