Ghrelin Inhibits Proinflammatory Responses and Nuclear Factor-κB Activation in Human Endothelial Cells

Abstract

Background-Ghrelin is a novel growth hormone-releasing peptide that has been shown to improve cachexia in heart failure and cancer and to ameliorate the hemodynamic and metabolic disturbances in septic shock. Because cytokine-induced inflammation is critical in these pathological states and because the growth hormone secretagogue receptor has been identified in blood vessels, we examined whether ghrelin inhibits proinflammatory responses in human endothelial cells in vitro and after administration of endotoxin to rats in vivo. Methods and Results-Human umbilical vein endothelial cells (HUVECs) were treated with or without tumor necrosis factor-␣ (TNF-␣), and induction of proinflammatory cytokines and mononuclear cell adhesion were determined. Ghrelin (0.1 to 1000 ng/mL) inhibited both basal and TNF-␣-induced cytokine release and mononuclear cell binding. Intravenous administration of ghrelin also inhibited endotoxin-induced proinflammatory cytokine production in rats in vivo. Ghrelin inhibited H 2 O 2 -induced cytokine release in HUVECs, suggesting that the peptide blocks redox-mediated cellular signaling. Moreover, ghrelin inhibited basal and TNF-␣-induced activation of nuclear factor-B. Des-acyl ghrelin had no effect on TNF-␣-induced cytokine production in HUVECs, suggesting that the antiinflammatory effects of ghrelin require interaction with endothelial growth hormone secretagogue receptors. Conclusions-Ghrelin inhibits proinflammatory cytokine production, mononuclear cell binding, and nuclear factor-B activation in human endothelial cells in vitro and endotoxin-induced cytokine production in vivo. These novel antiinflammatory actions of ghrelin suggest that the peptide could play a modulatory role in atherosclerosis, especially in obese patients, in whom ghrelin levels are reduced.

Ghrelin Gene Products in Acute and Chronic Inflammation

“…Macrophage lineage, activated endothelium, human lymphocytes and thymus express several somatostatin receptor subtypes and the MrgX2 receptor (van Hagen et al 2008), suggesting that cortistatin might represent the link between ghrelin and the somatostatin/ cortistatin system in the immune system. Ghrelin, Unacylated Ghrelin, and Obestatin Secretion and Activity in Acute and Chronic Inflammatory States Several studies on the anti-inflammatory activity of ghrelin showed that only the acylated peptide was able to decrease the expression and production of proinflammatory cytokines: interleukin (IL)-1a, IL-1b, IL-6, and tumor necrosis factor (TNF)-a by activated T cells and by lipopolysaccharide (LPS)-activated monocytes and microglia (Dixit et al 2004;Li et al 2004;Theil et al 2009). Ghrelin has been shown to prevent also microglial activation in a mouse model of Parkinson's disease by inhibiting the expression of TNF-a and IL-1b induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and to prevent the release of TNF-a and IL-1b from microglia treated with threohydroxyaspartate (Lee et al 2012;Moon et al 2009).…”

“…The effect of ghrelin on pro-inflammatory cytokines induction and release has been related, in several studies, to a suppression of the expression and/or activity of the transcription factor NF-jB (Barazzoni et al 2014;Hou et al 2009;Konturek et al 2006;Li et al 2004;Liu et al 2010;Peng et al 2012;Slomiany and Slomiany 2013;Wang et al 2012;Waseem et al 2008;Wu et al 2005;Yuan et al 2009;Zhou and Xue 2009). However, it has been proposed that in some circumstances and with some cell types, ghrelin may act as a pro-inflammatory peptide inducing, rather than reducing, NF-jB expression and proinflammatory IL-8 secretion (Kwan et al 2010;Rezaeian et al 2012;Sung et al 2011;Zhao et al 2006).…”

“…Although unacylated ghrelin is not able to induce the same effects of the acylated peptide in activated T cells and endothelial cells, (Dixit et al 2004;Li et al 2004), nevertheless it impairs TNF-a induction in muscles and livers of rats undergoing burn injury and reduces, in myotubes in vitro, the activation of NF-jB induced by treatment with pro-inflammatory cytokines (Sheriff et al 2012).…”

“…Ghrelin increases the efflux of cholesterol from macrophages through regulation of peroxisome proliferator-activated receptor c, thus inhibiting the formation of foam cells and reducing the development of atherosclerotic lesions (Cheng et al 2010;Demers et al 2009). In TNF-a-treated human endothelial cells, ghrelin inhibits proinflammatory cytokine production, NF-jB activation, expression of adhesion molecules, and adhesion of monocytes (Kellokoski et al 2009;Li et al 2004). Diversely, without TNF-a stimulation, ghrelin shows a pro-atherogenic activity (Kellokoski et al 2009;Skilton et al 2005).…”

Endothelial dysfunction and arterial abnormalities in childhood obesity

“…Resistin levels are associated with circulating levels of inflammatory markers including C-reactive protein, 92 whereas ghrelin appears to have anti-inflammatory effects by inhibiting the production of interleukin-8 and monocyte chemoattractant chemokine-1. 93 Leptin has prothrombotic effects, 94,95 and also increases oxidative stress. 96 Adiponectin has wide-ranging antiatherosclerotic effects including upregulating endothelial nitric oxide synthase, decreasing superoxide production by endothelial cells and inhibiting lipid accumulation in human monocyte-derived macrophages.…”