title: 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.
authors.affiliation: Department of Molecular and Clinical Medicine/Diabetes, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Wallerstedt
authors.forename: Madeléne
authors.initials: M
authors.lastname: Sandqvist
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.forename: Christian X
authors.initials: CX
authors.lastname: Andersson
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D017931:DNA Primers; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007328:Insulin / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D051745:Protein Kinase C-delta / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection
chemical_list: D017931:DNA Primers; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051745:Protein Kinase C-delta