Kim Hyo Young, Kim Jae Ryong, Kim Hee Sun
Department of Microbiology College of Medicine, Yeungnam University, Daegu, Korea.
J Microbiol Biotechnol. 2008 Jun;18(6):1170-8.
The cyclopentenone prostaglandins (cyPGs) prostaglandin A1 (PGA1) and 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) have been reported to exhibit antiinflammatory activity in activated monocytes/macrophages. However, the effects of these two cyPGs on the expression of cytokine genes may differ. In this study, we investigated the mechanism of action of PGA1 in lipopolysaccharide (LPS)-induced expression of interleukin (IL)-10 mRNA in mouse peritoneal macrophages. 15d-PGJ2 inhibited expression of LPSinduced IL-10, whereas PGA1 increased LPS-induced IL-10 expression. This synergistic effect of PGA1 on LPS-induced IL-10 expression reached a maximum as early as 2 h after simultaneous PGA1 and LPS treatment (PGA1/LPS), and did not require new protein synthesis. The synergistic effect of PGA1 was inhibited by GW9662, a specific peroxisome proliferator-activated receptor (PPAR) antagonist, and Bay-11-7082, a NF-kappaB inhibitor. The extracellular signalregulated kinases (ERK) inhibitor PD98059 increased the expression of PGA1/LPS-induced IL-10 mRNA, rather than inhibiting the IL-10 expression. Moreover, PGA1 inhibited LPS-induced ERK phosphorylation. The synergistic effect of PGA1 on LPS-induced IL-10 mRNA and protein production was inhibited by p38 inhibitor PD169316, and PGA1 increased LPS-induced p38 phosphorylation. In the case of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK), the SAPK/JNK inhibitor SP600125 did not inhibit IL-10 mRNA synthesis but inhibited the production of IL-10 protein remarkably. These results suggest that the synergistic effect of PGA1 on LPS-induced IL-10 expression is NF-kappaB-dependent and mediated by mitogen-activated protein (MAP) kinases, p38, and SAPK/ JNK signaling pathways, and also associated with the PPARgamma pathway. Our data may provide more insight into the diverse mechanisms of PGA1 effects on the expression of cytokine genes.
据报道，环戊烯酮前列腺素（cyPGs）前列腺素A1（PGA1）和15-脱氧-12,14-前列腺素J2（15d-PGJ2）在活化的单核细胞/巨噬细胞中具有抗炎活性。然而，这两种cyPGs对细胞因子基因表达的影响可能不同。在本研究中，我们研究了PGA1在脂多糖（LPS）诱导的小鼠腹腔巨噬细胞白细胞介素（IL）-10 mRNA表达中的作用机制。15d-PGJ2抑制LPS诱导的IL-10表达，而PGA1增加LPS诱导的IL-10表达。PGA1对LPS诱导的IL-10表达的这种协同作用在PGA1和LPS同时处理（PGA1/LPS）后最早2小时达到最大值，并且不需要新的蛋白质合成。PGA1的协同作用被特异性过氧化物酶体增殖物激活受体（PPAR）拮抗剂GW9662和NF-κB抑制剂Bay-11-7082抑制。细胞外信号调节激酶（ERK）抑制剂PD98059增加了PGA1/LPS诱导的IL-10 mRNA的表达，而不是抑制IL-10的表达。此外，PGA1抑制LPS诱导的ERK磷酸化。PGA1对LPS诱导的IL-10 mRNA和蛋白质产生的协同作用被p38抑制剂PD169316抑制，并且PGA1增加LPS诱导的p38磷酸化。在应激激活蛋白激酶/c-Jun NH2末端激酶（SAPK/JNK）的情况下，SAPK/JNK抑制剂SP600125不抑制IL-10 mRNA合成，但显著抑制IL-10蛋白质的产生。这些结果表明，PGA1对LPS诱导的IL-10表达的协同作用是NF-κB依赖性的，由丝裂原活化蛋白（MAP）激酶、p38和SAPK/JNK信号通路介导，并且还与PPARγ通路相关。我们的数据可能为PGA1对细胞因子基因表达影响的多种机制提供更多见解。
