Crosstalk between different family members: IL27 recapitulates IFNγ responses in HCC cells, but is inhibited by IL6-type cytokines

Biochim Biophys Acta Mol Cell Res. 2017 Mar;1864(3):516-526. doi: 10.1016/j.bbamcr.2016.12.006. Epub 2016 Dec 9.

Abstract

Interleukin-27 (IL27) is a type-I-cytokine of the IL6/IL12 family predominantly secreted by activated macrophages and dendritic cells. In the liver, IL27 expression was observed to be upregulated in patients with hepatitis B, and sera of hepatocellular carcinoma (HCC) patients contain significantly elevated levels of IL27 compared to healthy controls or patients with hepatitis and/or liver cirrhosis. In this study, we show that IL27 induces STAT1 and STAT3 phosphorylation in 5 HCC lines and 3 different types of non-transformed liver cells. We were especially interested in the relevance of the IL27-induced STAT3 activation in liver cells. Thus, we compared the IL27 responses with those induced by IFNγ (STAT1-dominated response) or IL6-type cytokines (IL6, hyper-IL6 (hy-IL6) or OSM) (STAT3-dominated response) by microarray analysis and find that in HCC cells, IL27 induces an IFNγ-like, STAT1-dependent transcriptional response, but we do not find an effective STAT3-dependent response. Validation experiments corroborate the finding from the microarray evaluation. Interestingly, the availability of STAT1 seems critical in the shaping of the IL27 response, as the siRNA knock-down of STAT1 revealed the ability of IL27 to induce the acute-phase protein γ-fibrinogen, a typical IL6 family characteristic. Moreover, we describe a crosstalk between the signaling of IL6-type cytokines and IL27: responses to the gp130-engaging cytokine IL27 (but not those to IFNs) can be inhibited by IL6-type cytokine pre-stimulation, likely by a SOCS3-mediated mechanism. Thus, IL27 recapitulates IFNγ responses in liver cells, but differs from IFNγ by its sensitivity to SOCS3 inhibition.

Keywords: Hepatocellular carcinoma; IFNγ; IL27; IL6-type cytokines; SOCS3; STAT transcription factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / immunology
  • Fibrinogen / genetics
  • Fibrinogen / immunology
  • Gene Expression Regulation
  • Hepatocytes / immunology*
  • Hepatocytes / pathology
  • Humans
  • Interferon-gamma / genetics*
  • Interferon-gamma / immunology
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-6 / genetics*
  • Interleukin-6 / immunology
  • Interleukins / genetics
  • Interleukins / immunology*
  • Microarray Analysis
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / immunology
  • STAT1 Transcription Factor / antagonists & inhibitors
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / immunology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / immunology*

Substances

  • IL6 protein, human
  • Interleukin-6
  • Interleukins
  • MYDGF protein, human
  • RNA, Small Interfering
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • Cytokine Receptor gp130
  • Interleukin-12
  • Interferon-gamma
  • Fibrinogen