title: Crosstalk between different family members: IL27 recapitulates IFNγ responses in HCC cells, but is inhibited by IL6-type cytokines.
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.
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Signal Transduction Laboratory, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: catherine.rolvering@uni.lu.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rolvering
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Signal Transduction Laboratory, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: andreas_zimmer@web.de.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Zimmer
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Signal Transduction Laboratory, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: ineskozar91@gmail.com.
authors.forename: Ines
authors.initials: I
authors.lastname: Kozar
authors.affiliation: University Hospital Würzburg, Medical Clinic II, Division of Hepatology, Grombühlstr. 12, D-97080 Würzburg, Germany. Electronic address: heike.hermanns@virchow.uni-wuerzburg.de.
authors.forename: Heike M
authors.initials: HM
authors.lastname: Hermanns
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Molecular Disease Mechanisms Laboratory, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: elisabeth.letellier@uni.lu.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Letellier
authors.affiliation: Genomics Research Laboratory, Dept. of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, L1526 Luxembourg, Luxembourg. Electronic address: laurent.vallar@lih.lu.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.affiliation: Genomics Research Laboratory, Dept. of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, L1526 Luxembourg, Luxembourg. Electronic address: petr.nazarov@lih.lu.
authors.forename: Petr V
authors.initials: PV
authors.lastname: Nazarov
authors.affiliation: Genomics Research Laboratory, Dept. of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, L1526 Luxembourg, Luxembourg. Electronic address: nathalie.nicot@lih.lu.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nicot
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Bioinformatics Core Facility, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: aurelien.ginolhac@uni.lu.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Ginolhac
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Molecular Disease Mechanisms Laboratory, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: serge.haan@uni.lu.
authors.forename: Serge
authors.initials: S
authors.lastname: Haan
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Signal Transduction Laboratory, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: iris.behrmann@uni.lu.
authors.forename: Iris
authors.initials: I
authors.lastname: Behrmann
authors.affiliation: University of Luxembourg, Life Sciences Research Unit - Signal Transduction Laboratory, 6, Avenue du Swing, L4367 Belvaux, Luxembourg. Electronic address: claude.haan@uni.lu.
authors.forename: Claude
authors.initials: C
authors.lastname: Haan
mesh_terms: D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D005340:Fibrinogen / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D046228:Microarray Analysis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000276:immunology*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D007378:Interleukins; C464565:MYDGF protein, human; D034741:RNA, Small Interfering; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050822:Cytokine Receptor gp130; D018664:Interleukin-12; D007371:Interferon-gamma; D005340:Fibrinogen
keywords: Hepatocellular carcinoma; IFNγ; IL27; IL6-type cytokines; SOCS3; STAT transcription factors