Title: Expression of suppressors of cytokine signaling during liver regeneration.
Authors: Campbell, J S; Prichard, L; Schaper, F; Schmitz, J; Stephenson-Famy, A; Rosenfeld, M E; Argast, G M; Heinrich, P C; Fausto, N
Published In J Clin Invest, (2001 May)
Abstract: The cytokines TNF and IL-6 play a critical role early in liver regeneration following partial hepatectomy (PH). Since IL-6 activates signal transducers and activators of transcription (STATs), we examined whether the suppressors of cytokine signaling (SOCS) may be involved in terminating IL-6 signaling. We show here that SOCS-3 mRNA is induced 40-fold 2 hours after surgery. SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable. SOCS-3 induction after PH is transient and correlates with a decrease in STAT-3 DNA binding and a loss of tyrosine 705 phosphorylation. This response is markedly reduced in IL-6 knockout (KO) mice. TNF injection induces SOCS-3 mRNA in wild-type mice (albeit weakly compared with the increase observed after PH) but not in TNF receptor 1 or IL-6 KO mice. In contrast, IL-6 injection induces SOCS-3 in these animals, demonstrating a requirement for IL-6 in SOCS-3 induction. IL-6 injection into wild-type mice also induces SOCS-1, -2, and CIS mRNA, in addition to SOCS-3. Together, these results suggest that SOCS-3 may be a key component in downregulating STAT-3 signaling after PH and that SOCS-3 mRNA levels in the regenerating liver are regulated by IL-6.
PubMed ID: 11375418
MeSH Terms: Animals; Antigens, CD/genetics; DNA-Binding Proteins/metabolism; Gene Expression Regulation; Hepatectomy; Interleukin-6/immunology*; Liver Regeneration/immunology*; Mice; Mice, Knockout; Proteins/genetics*; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor/genetics; Repressor Proteins*; STAT3 Transcription Factor; Signal Transduction; Suppressor of Cytokine Signaling Proteins; Trans-Activators/metabolism; Transcription Factors*; Tumor Necrosis Factor-alpha/immunology*