Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells
Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells
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DOI：
10.3390/ijms17081359
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发表时间：
2016-08-01
影响因子：
5.6
通讯作者：
Wu, Yuh-Lin
中科院分区：
文献类型：
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作者：
Chao, Yi-Ning;Sun, David;Wu, Yuh-Lin
环氧合酶-2 （COX-2）和白细胞介素-8 （IL-8）是排卵过程中两种重要的炎症介质。生长素可能通过生长激素促分泌受体调节炎症信号。我们利用蛋白激酶C （PKC）激活剂phorbol 12,13 -didecanoate （PDD）和合成的ghrelin类似物生长激素释放肽-2 （GHRP-2）研究了ghrelin在KGN人卵巢颗粒细胞中的作用。GHRP-2可减弱pdd诱导的蛋白和mRNA表达、COX-2和IL-8基因启动子活性以及前列腺素E2 （PGE2）和IL-8的分泌。GHRP-2通过蛋白酶体和溶酶体途径促进pdd诱导的COX-2和IL-8蛋白的降解。pdd介导的COX-2的产生通过活化B细胞的p38、c-Jun n末端激酶（JNK）、细胞外信号调节激酶（ERK）和核因子kappa-轻链增强子（NF-kappa B）途径起作用；pdd介导的IL-8产生通过p38、JNK和ERK途径起作用。GHRP-2降低了pdd诱导的p38和JNK磷酸化、激活蛋白1 （AP-1）报告因子激活以及pdd诱导的NF-kappa B核易位和报告因子激活。丝裂原活化蛋白激酶磷酸酶-1 （MKP-1）和蛋白磷酸酶2 （PP2A）抑制剂降低了GHRP-2对pdd诱导的COX-2和IL-8表达的抑制作用。我们的研究结果表明，ghrelin （GHRP-2）在pkc介导的颗粒细胞炎症中具有抗炎作用，至少部分原因是其抑制pkc诱导的p38、JNK和NF-kappa B的激活，可能是通过靶向mgp -1和PP2A。
Cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) are two important inflammatory mediators in ovulation. Ghrelin may modulate inflammatory signaling via growth hormone secretagogue receptors. We investigated the role of ghrelin in KGN human ovarian granulosa cells using protein kinase C (PKC) activator phorbol 12, 13-didecanoate (PDD) and synthetic ghrelin analog growth hormone releasing peptide-2 (GHRP-2). GHRP-2 attenuated PDD-induced expression of protein and mRNA, the promoter activity of COX-2 and IL-8 genes, and the secretion of prostaglandin E2 (PGE2) and IL-8. GHRP-2 promoted the degradation of PDD-induced COX-2 and IL-8 proteins with the involvement of proteasomal and lysosomal pathways. PDD-mediated COX-2 production acts via the p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) pathways; PDD-mediated IL-8 production acts via the p38, JNK and ERK pathways. GHRP-2 reduced the PDD-induced phosphorylation of p38 and JNK and activator protein 1 (AP-1) reporter activation and PDD-induced NF-kappa B nuclear translocation and reporter activation. The inhibitors of mitogen-activated protein kinase phosphatase-1 (MKP-1) and protein phosphatase 2 (PP2A) reduced the inhibitory effect of GHRP-2 on PDD-induced COX-2 and IL-8 expression. Our findings demonstrate an anti-inflammatory role for ghrelin (GHRP-2) in PKC-mediated inflammation of granulosa cells, at least in part, due to its inhibitory effect on PKC-induced activation of p38, JNK and NF-kappa B, possibly by targeting to MKP-1 and PP2A.