UNLABELLED: Partial hepatectomy (PH) consistently results in an early increase of circulating interleukin-6 (IL-6), which is thought to play a major role in liver regeneration. Activation of this cytokine after PH requires the adaptor protein, MyD88, but the specific MyD88-related receptors involved remain unidentified. It is also unknown whether the magnitude of IL-6 elevation determines the extent of subsequent hepatocyte proliferation. Here, we uncovered artifacts in the assessment of circulating IL-6 levels when using cardiac puncture in mice after PH. By using retro-orbital bleed sampling, we show that the circulating levels of IL-6 after PH were not directly correlated with the extent of hepatocyte DNA synthesis in individual mice. The IL-6 increase after PH was attenuated in all lipopolysaccharide-hyporesponsive mouse strains studied (e.g., C3H/HeJ, Tlr4 null, Cd14 null, Tlr2,4,9 null, and Tlr2,4-Caspase1 null) and was severely abrogated in Myd88 null mice. Despite attenuated IL-6 levels, Tlr4 null mice showed normal signaling downstream of IL-6 and normal hepatocyte proliferation. In contrast, Myd88 null mice showed severe impairments in signal transducer and activator of transcription 3 phosphorylation and Socs3 induction, but had enhanced and prolonged extracellular signal-related kinase 1 and 2 phosphorylation in the first 6 hours after PH. Unexpectedly, these changes were associated with accelerated initiation of hepatocyte proliferation, as assessed by hepatocyte bromodeoxyuridine incorporation, phospho-histone H3 immunostaining, and cyclin E and A protein expression. CONCLUSION: TLR-4 signaling contributes to IL-6 activation after PH, but the Tlr4-independent component appears sufficient for ensuring intact signaling downstream of IL-6. The lack of correlation between IL-6 levels and hepatocyte proliferation after PH, and the accelerated start of hepatocyte proliferation in Myd88 null mice despite abrogated cytokine activation, may highlight relevant antiproliferative effects of IL-6 signaling, possibly via Socs3, in the regulation of liver regeneration.
UNLABELLED: Partial hepatectomy (PH) consistently results in an early increase of circulating interleukin-6 (IL-6), which is thought to play a major role in liver regeneration. Activation of this cytokine after PH requires the adaptor protein, MyD88, but the specific MyD88-related receptors involved remain unidentified. It is also unknown whether the magnitude of IL-6 elevation determines the extent of subsequent hepatocyte proliferation. Here, we uncovered artifacts in the assessment of circulating IL-6 levels when using cardiac puncture in mice after PH. By using retro-orbital bleed sampling, we show that the circulating levels of IL-6 after PH were not directly correlated with the extent of hepatocyte DNA synthesis in individual mice. The IL-6 increase after PH was attenuated in all lipopolysaccharide-hyporesponsive mouse strains studied (e.g., C3H/HeJ, Tlr4 null, Cd14 null, Tlr2,4,9 null, and Tlr2,4-Caspase1 null) and was severely abrogated in Myd88 null mice. Despite attenuated IL-6 levels, Tlr4 null mice showed normal signaling downstream of IL-6 and normal hepatocyte proliferation. In contrast, Myd88 null mice showed severe impairments in signal transducer and activator of transcription 3 phosphorylation and Socs3 induction, but had enhanced and prolonged extracellular signal-related kinase 1 and 2 phosphorylation in the first 6 hours after PH. Unexpectedly, these changes were associated with accelerated initiation of hepatocyte proliferation, as assessed by hepatocyte bromodeoxyuridine incorporation, phospho-histone H3 immunostaining, and cyclin E and A protein expression. CONCLUSION:TLR-4 signaling contributes to IL-6 activation after PH, but the Tlr4-independent component appears sufficient for ensuring intact signaling downstream of IL-6. The lack of correlation between IL-6 levels and hepatocyte proliferation after PH, and the accelerated start of hepatocyte proliferation in Myd88 null mice despite abrogated cytokine activation, may highlight relevant antiproliferative effects of IL-6 signaling, possibly via Socs3, in the regulation of liver regeneration.
Authors: S E Nicholson; D De Souza; L J Fabri; J Corbin; T A Willson; J G Zhang; A Silva; M Asimakis; A Farley; A D Nash; D Metcalf; D J Hilton; N A Nicola; M Baca Journal: Proc Natl Acad Sci U S A Date: 2000-06-06 Impact factor: 11.205
Authors: J S Campbell; L Prichard; F Schaper; J Schmitz; A Stephenson-Famy; M E Rosenfeld; G M Argast; P C Heinrich; N Fausto Journal: J Clin Invest Date: 2001-05 Impact factor: 14.808
Authors: Xavier Aldeguer; Fotini Debonera; Abraham Shaked; Alyssa M Krasinkas; Andrew E Gelman; Xingyi Que; Gideon A Zamir; Shungo Hiroyasu; Kellen K Kovalovich; Rebecca Taub; Kim M Olthoff Journal: Hepatology Date: 2002-01 Impact factor: 17.425
Authors: Ling Xia; Lijuan Wang; Alicia S Chung; Stanimir S Ivanov; Mike Y Ling; Ana M Dragoi; Adam Platt; Tona M Gilmer; Xin-Yuan Fu; Y Eugene Chin Journal: J Biol Chem Date: 2002-06-17 Impact factor: 5.157
Authors: Torsten Wuestefeld; Christian Klein; Konrad L Streetz; Ulrich Betz; Jörg Lauber; Jan Buer; Michael P Manns; Werner Müller; Christian Trautwein Journal: J Biol Chem Date: 2002-12-30 Impact factor: 5.157
Authors: Kimberly J Riehle; Melissa M Johnson; Fredrik Johansson; Renay L Bauer; Brian J Hayes; Debra G Gilbertson; Aaron C Haran; Nelson Fausto; Jean S Campbell Journal: Biochim Biophys Acta Date: 2013-11-19