Toll-like receptor 4 and myeloid differentiation factor 88 provide mechanistic insights into the cause and effects of interleukin-6 activation in mouse liver regeneration

• DOI: 10.1002/hep.24420
• Publication Date: 2011-05-13T16:58:47Z
• Authors: Javier Vaquero; Jean S. Campbell; Jamil Haque; Ryan S. McMahon; Kimberly J. Riehle; Renay L. Bauer; Nelson Fausto
• Keywords: Liver Regeneration

Partial hepatectomy (PH) consistently results in an early increase of circulating interleukin-6 (IL-6), which is thought to play a major role liver regeneration. Activation this cytokine after PH requires the adaptor protein, MyD88, but specific MyD88-related receptors involved remain unidentified. It also unknown whether magnitude IL-6 elevation determines extent subsequent hepatocyte proliferation. Here, we uncovered artifacts assessment levels when using cardiac puncture mice PH. By retro-orbital bleed sampling, show that were not directly correlated with DNA synthesis individual mice. The was attenuated all lipopolysaccharide-hyporesponsive mouse strains studied (e.g., C3H/HeJ, Tlr4 null, Cd14 Tlr2,4,9 and Tlr2,4-Caspase1 null) severely abrogated Myd88 null Despite levels, showed normal signaling downstream In contrast, severe impairments signal transducer activator transcription 3 phosphorylation Socs3 induction, had enhanced prolonged extracellular signal-related kinase 1 2 first 6 hours Unexpectedly, these changes associated accelerated initiation proliferation, as assessed by bromodeoxyuridine incorporation, phospho-histone H3 immunostaining, cyclin E A protein expression. Conclusion: TLR-4 contributes activation PH, -independent component appears sufficient for ensuring intact IL-6. lack correlation between proliferation start despite activation, may highlight relevant antiproliferative effects signaling, possibly via , regulation (Hepatology 2011;)