Expression of suppressors of cytokine signaling during liver regeneration

The cytokines TNF and IL-6 play a critical role early in liver regeneration following partial hepatectomy (PH). Since IL-6 activates signal transducer s and activators of transcription (STATs), we examined whether the suppress ors of cyokine signaling (SOCS) maybe involved in terminating LL-G signalin g. 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 ST AT-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 inj ection 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 sugges t that SOCS-3 may be a key component in downregulating STAT-3 signaling aft er PH and that SOCS-3 mRNA levels in the regenerating Liver are regulated b y IL-6.