Stat1-independent induction of SOCS-3 by interferon-gamma is mediated by sustained activation of Stat3 in mouse embryonic fibroblasts.
Using microarray technology, we previously demonstrated that IFN-gamma induces suppressor of cytokine signaling-3 (SOCS-3) in Stat1-/- mouse embryonic fibroblasts and bone marrow-derived macrophages. In this study, we have investigated the mechanism by which SOCS-3 is induced by Stat1-independent signal transduction pathway. Tyrosine kinases Jak1 and Jak2 are required for SOCS-3 induction by IFN-gamma in mouse embryonic fibroblasts. IFN-gamma stimulated strong and sustained activation of Stat1 whereas Stat3 activation was weak and transient in wild-type fibroblasts. In contrast, Stat3 is activated strongly and in a sustained manner in Stat1-/- fibroblasts. The Src kinase inhibitor SU6656 suppressed IFN-gamma activation of Stat3 in both wild-type and Stat1-/- fibroblasts. However, SU6656 inhibited IFN-gamma induction of SOCS-3 completely in Stat1-/- but not in wild-type fibroblasts. Knock down of Stat3 by short interfering RNA abrogated Stat3 activation and SOCS-3 induction by IFN-gamma in Stat1-/- fibroblasts. In human fibrosarcoma cell line 2fTGH, IFN-gamma activated Stat1 but not Stat3. SOCS-3 induction by IFN-gamma is strictly Stat1-dependent. The Stat1 docking site is required for SOCS-3 induction by IFN-gamma in human lung adenocarcinoma cells. We propose a model in which sustained activation of Stat1 or Stat3 mediates SOCS-3 induction by IFN-gamma in wild-type and Stat1-/- mouse embryonic fibroblasts, respectively.
Ramana
Chilakamarti V
CV
Department of Medicine, Yale University, New Haven, CT 06516, USA. rvc5@email.med.yale.edu
Kumar
Aseem
A
Enelow
Richard
R
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491411:Socs3 protein, mouse; C494080:Stat1 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; D012313:RNA; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases