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 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.
Campbell
J S
JS
University of Washington, Department of Pathology, Seattle, Washington 98195, USA.
Prichard
L
L
Schaper
F
F
Schmitz
J
J
Stephenson-Famy
A
A
Rosenfeld
M E
ME
Argast
G M
GM
Heinrich
P C
PC
Fausto
N
N
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006498:Hepatectomy; D015850:Interleukin-6 / Q000276:immunology*; D008115:Liver Regeneration / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha