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Int. J. Mol. Sci. 2016, 17(8), 1359; doi:10.3390/ijms17081359

Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells

1
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan
2
Department of Obstetrics and Gynecology, Cheng Hsin General Hospital, Taipei 11221, Taiwan
3
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Kwong-Kwok Wong
Received: 27 June 2016 / Revised: 15 August 2016 / Accepted: 16 August 2016 / Published: 19 August 2016
(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies)
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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. View Full-Text
Keywords: granulosa cell; inflammation; cyclooxygenase-2; interleukin-8; ghrelin; growth hormone releasing peptide-2 granulosa cell; inflammation; cyclooxygenase-2; interleukin-8; ghrelin; growth hormone releasing peptide-2
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MDPI and ACS Style

Chao, Y.-N.; Sun, D.; Peng, Y.-C.; Wu, Y.-L. Growth Hormone Releasing Peptide-2 Attenuation of Protein Kinase C-Induced Inflammation in Human Ovarian Granulosa Cells. Int. J. Mol. Sci. 2016, 17, 1359.

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