Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-κB, and STAT3 signaling pathways
Creators: name: Wanninger, Josef
name: Neumeier, Markus
name: Weigert, Johanna
name: Bauer, Sabrina
name: Weiss, Thomas S.
name: Schäffler, Andreas
name: Krempl, Corinna
name: Bleyl, Cornelia
name: Aslanidis, Charalampos
name: Schölmerich, Jürgen
name: Buechler, Christa
Publisher: name: Universität Regensburg
Year: 2009
Subjects: subject: adiponectin hepatocyte nuclear factor-κB adiponectin receptor 1 STAT3 extracellular signal-regulated kinase mitogen-activated protein kinase
subject: 610 Medizin

description: Abstract

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-κB in primary hepatocytes and pharmacological inhibition of NF-κB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with “STAT3 Inhibitor VI,” however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-κB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.

adiponectin is an adipocyte-derived protein with antidiabetic and hepatoprotective properties, but systemic levels are reduced in obesity, hepatic steatosis, and liver fibrosis (1, 32, 45, 48). Adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) are expressed in hepatocytes (23, 24, 44) and mediate the hepatoprotective effects of adiponectin, but contradictory data have been published regarding the abundance of adiponectin receptors in injured liver (2, 23, 39). Binding of adiponectin to AdipoR2 activates the peroxisome proliferator activated receptor-α thereby stimulating β-oxidation, whereas AdipoR1 is involved in the activation of the AMP-activated protein kinase, p38 mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-κB (34, 44). Both receptors activate extracellular signal-regulated kinase (ERK) 1/2 in Hek293 cells through a Src/Ras pathway and stimulate proliferation (16).

In animal models, it has been shown that adiponectin is protective in endotoxin- and concanavalin A-induced hepatotoxicity (19, 43). Adiponectin ameliorates inflammation by lowering the release of proinflammatory cytokines; it inhibits the activation of hepatic stellate cells and antagonizes hepatocytic cell death (19, 32, 43).

CXC chemokines act as survival factors, and adiponectin induces CXCL8, a chemokine that exerts mitogenic and antiapoptotic functions, in monocytes and endothelial cells (29, 40). CXCL8 administration protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis and growth arrest of hepatocytes (26). Similar protective mechanisms have been observed in mice with hepatic overexpression of the CXCL8 ortholog KC where liver injury was induced by galactosamine and endotoxin (8). KC is upregulated by the hepatoprotective cytokine interleukin (IL)-6 via the activation of the IL6-gp130-STAT3 pathway, and recombinant KC reduces serum aminotransferase levels in mice with concanavalin A-mediated liver damage (14).

Besides these antiapoptotic and hepatoprotective effects, CXCL8 is a chemoattractant and activator for neutrophils, basophils, and T cells that may aggravate liver fibrosis (28). Despite 100-fold elevated KC serum levels in the IL-6-treated mice, an influx of polymorphonuclear cells in the liver was not observed (14).

Systemic CXCL8 is elevated in obesity (33) and patients with nonalcoholic fatty liver disease (NAFLD) and is suggested to contribute to the pathogenesis of these disorders (10). NAFLD is often referred to as the hepatic manifestation of the metabolic syndrome, and excess hepatic lipid storage represents a first hit that predisposes the liver to subsequent damage (37). Incubation of hepatocytes with palmitic acid may be used as an in vitro model for hepatic steatosis and, despite an induction of CXCL8 in the lipid-loaded cells, an enhanced apoptosis was observed (12).

Taken together, these data indicate that the function of CXCL8 has not been fully characterized, and its tightly controlled activity may be essential to ensure the protective effects of this chemokine. We have recently shown that adiponectin induces CXCL8 in primary human monocytes by a pathway involving the p38 MAPK, and similar results were published for endothelial cells (29, 40). In the current study, our goal was to investigate whether adiponectin enhances CXCL8 release in hepatocytes and to identify the signaling pathways involved.