title: Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells.
abstract: 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-κB) 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-κB 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-κB, possibly by targeting to MKP-1 and PP2A.
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan. stanley11306@hotmail.com.
authors.forename: Yi-Ning
authors.initials: YN
authors.lastname: Chao
authors.affiliation: Department of Obstetrics and Gynecology, Cheng Hsin General Hospital, Taipei 11221, Taiwan. shineway@hotmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan. pychun@vghtc.gov.tw.
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Peng
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan. ylwu@ym.edu.tw.
authors.forename: Yuh-Lin
authors.initials: YL
authors.lastname: Wu
mesh_terms: D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D054439:Ghrelin / Q000378:metabolism; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D054439:Ghrelin; D016209:Interleukin-8; D009842:Oligopeptides; D010703:Phorbol Esters; D018808:Transcription Factor AP-1; C008876:phorbol-12,13-didecanoate; C091874:growth hormone-releasing peptide-2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011493:Protein Kinase C
keywords: cyclooxygenase-2; ghrelin; granulosa cell; growth hormone releasing peptide-2; inflammation; interleukin-8