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.
Highlights
Inflammation plays an important role in the host defense system that occurs in response to internal or external stimuli; it functions to counteract the insults exerted by these stimuli [1]
This study aimed to clarify the signaling mechanisms targeted by growth hormone releasing peptide-2 (GHRP-2) that are involved in the protein kinase C (PKC)-regulated production of COX-2, prostaglandin E2 (PGE2) and IL-8
In this study we demonstrated that the PKC-mediated COX-2 expression involves, at least in part, all of the mitogen-activated protein kinases (MAPKs) (p38, extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK)) as well as NF-κB, while IL-8 expression involves, at least in part, all of the MAPKs pathways but not the NF-κB (Figure 6)
Summary
Inflammation plays an important role in the host defense system that occurs in response to internal or external stimuli; it functions to counteract the insults exerted by these stimuli [1]. Ghrelin was shown to improve the bovine blastocyst formation [25] and to enhance the maturation of bovine oocytes [26], but it was reported to inhibit the GnRH-induced preovulatory gonadotropin surge in dairy heifers [27] Accumulated findings from these studies indicate that ghrelin may play an important role in the ovarian system. The aim of the current study was to characterize how the ghrelin analog GHRP-2 affects the various PKC-mediated inflammatory cascades in human granulosa cells by monitoring the COX-2/prostaglandin E2 (PGE2) and the IL-8 pathways, which are two critical components to be associated with inflammation and known to be involved in ovarian physiology. This study aimed to clarify the signaling mechanisms targeted by GHRP-2 that are involved in the PKC-regulated production of COX-2, PGE2 and IL-8
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