Anti-inflammatory effect of insulin in the human hepatoma cell line HepG2 involves decreased transcription of IL-6 target genes and nuclear exclusion of FOXO1

Abstract

The liver is an important target for interleukin-6 (IL-6) action leading to an increased inflammatory response with impaired insulin signaling and action. The aims of this study are to address if insulin is anti-inflammatory and attenuates IL-6-induced inflammation in the human hepatoma cell line HepG2 and if this involves signal transducer and activator of transcription 3 (STAT3) signal transduction. It was found that insulin significantly reduced IL-6-induced gene transcription of serum amyloid 1 (SAA1), serum amyloid 2 (SAA2), haptoglobin, orosomucoid, and plasmin activator inhibitor-1 (PAI-1). However, the authors did not find any evidence that insulin inhibited IL-6 signal transduction, i.e., no effect of insulin was detected on STAT3 phosphorylation or its translocation to cell nucleus. The potential role of PKCδ was also analyzed but no evidence of its involvement was found. Taken together, these results suggest that the anti-inflammatory effect of insulin on IL-6 action is exerted at the level of the transcriptional activation of the genes. Further analysis revealed that insulin regulates nuclear localization of FOXO1, which is an important co-activator for STAT3 mediated transcription. Insulin induced nuclear exit and Thr24 phosphorylation of FOXO1, thus, inhibiting STAT3-mediated transcription.

FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes

“…This confirms a recent report of similar data [33]. The anti-inflammatory function of insulin would largely disappear due to severe blockage of the IRS1-AKT signaling.…”

“…It has recently been reported that insulin could attenuated IL-6-induced inflammation in HepG2 cells [33]. Selectively expressing constitutively active IKK-b in hepatocytes initiates hepatic and systemic IR due to parallel increases in cytokine signaling in liver and other tissues [34].…”

The Mechanism by Which Amentoflavone Improves Insulin Resistance in HepG2 Cells

“…Many studies suggested that insulin resistance is a process of chronic inflammation and that the inflammatory and PI3K-Akt signaling pathways interact to some degree [33]. In vivo , the presence of normal amounts of inflammatory cytokines does not cause damage.…”

Diabetes and Periodontal Disease: An Update for Health Care Providers

“…The liver is an important target for IL-6 action, leading to an increased inflammatory response with impaired insulin signaling and action and resultant decreased insulin production. 20 Patients with impaired insulin production are therefore unable to control for IL-6 activation and the enhanced inflammation induced by IL-6. 20 Elevated IL-6 serum levels have been identified in people with untreated chronic periodontitis.…”

“…20 Patients with impaired insulin production are therefore unable to control for IL-6 activation and the enhanced inflammation induced by IL-6. 20 Elevated IL-6 serum levels have been identified in people with untreated chronic periodontitis. 21 These studies suggest that the presence of elevated serum levels of pro-inflammatory cytokines in patients with type 2 diabetes caused by periodontitis may aggravate inflammatory responses in other organs commonly affected in patients with diabetes.…”