Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3

Abstract

Cytokines may cause an acquired growth hormone (GH) resistance in patients with inflammatory diseases. Anabolic effects of GH are mediated through activation of STAT5 transcription factors. We have reported that TNF-alpha suppresses hepatic GH receptor (GHR) gene expression, whereas the cytokine-inducible SH2-containing protein 1 (Cis)/suppressors of cytokine signaling (Socs) genes are upregulated by TNF-alpha and IL-6 and inhibit GH activation of STAT5. However, the relative importance of these mechanisms in inflammatory GH resistance was not known. We hypothesized that IL-6 would prevent GH activation of STAT5 and that this would involve Cis/Socs protein upregulation. GH +/- LPS was administered to TNF receptor 1 (TNFR1) or IL-6 null mice and wild-type (WT) controls. STAT5, STAT3, GHR, Socs 1-3, and Cis phosphorylation and abundance were assessed by using immunoblots, EMSA, and/or real time RT-PCR. TNF-alpha and IL-6 abundance were assessed by using ELISA. GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pretreatment prevented STAT5 activation in WT and TNFR1 null mice; however, STAT5 activation was preserved in IL-6 null mice. GHR abundance did not change with LPS administration. Inhibition of STAT5 activation by LPS was temporally associated with phosphorylation of STAT3 and upregulation of Cis and Socs-3 protein in WT and TNFR1 null mice; STAT3, Cis, and Socs-3 were not induced in IL-6 null mice. IL-6 inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may involve activation of STAT3. Therapies that block IL-6 may enhance GH signaling in inflammatory diseases.

Lipopolysaccharide (LPS) directly suppresses growth hormone receptor (GHR) expression through MyD88-dependent and -independent Toll-like receptor-4/MD2 complex signaling pathways

“…Similarly, IL-1 suppresses the promoter activity of the major GHR transcript via a Sp response element ). In contrast IL-6 suppresses GHR expression by upregulation of Cis and Socs-3, signaling molecules that inhibit GHR-STAT5 signaling pathways (Denson et al, 2003;Wang et al, 2002). The results of the current study demonstrate that LPS can directly inhibit GHR promoter activity.…”

“…Previous studies have established that GH insensitivity induced by LPS is characterized by down-regulation of GHR mRNA expression and up-regulation of expression of SOCS-3 mRNA, a canonical inhibitor of GHR signaling pathways (Yumet et al, 2006). The prevailing explanation for LPS-induced effects on the GHR mRNA expression is that these effects are secondary to LPS-induced generation of cytokines such as IL-1, IL-6 and TNF-α (Denson et al, 2003;). Thus Denson et al, reported on the molecular mechanisms involved in the pathogenesis of TNF-α-induced suppression of murine hepatic GHR .…”

GH activity and markers of inflammation: a crossover study in healthy volunteers treated with GH and a GH receptor antagonist

“…Moreover, a study on mice demonstrated that IGF1 administrated into the lateral ventricles of the brain completely blocked sickness behavior induced by TNFa injections (42). It is well documented that inflammation induces resistance to GH and IGF1 action with several studies indicating that elevated levels of IL6, TNFa, and IL1b per se are involved in these processes (9,43,44). Thus, there might be a reciprocal relationship between GH/IGF1 activity and pro-inflammatory cytokine action.…”

Endotoxin at low doses stimulates pituitary GH whereas it decreases IGF-I and IGF-binding protein-3 in rats

“…LPS administration decreases GHR gene expression in vitro and in vivo (Wolf et al 1996, Defalque et al 1999, and it is able to block the GH-responsive genes in the liver of hypophysectomized rats (Bergard et al 2000). The effect of LPS on the GHR in the liver was not evident 3 or 6 h after administration of 1 mg/kg LPS, although it inhibits GH activation of Stat5 (Mao et al 1999, Denson et al 2003. The authors concluded that the reduction in liver Stat5 activation was due to induction of postreceptor signaling inhibitors such as Cis and Socs-3 (Denson et al 2003).…”

“…The effect of LPS on the GHR in the liver was not evident 3 or 6 h after administration of 1 mg/kg LPS, although it inhibits GH activation of Stat5 (Mao et al 1999, Denson et al 2003. The authors concluded that the reduction in liver Stat5 activation was due to induction of postreceptor signaling inhibitors such as Cis and Socs-3 (Denson et al 2003). However, when using a higher LPS dose (7·5 mg/kg) it was also possible to observe a significant reduction in GHR mRNA (Defalque et al 1999).…”