STAT6 is required for the anti-inflammatory activity of interleukin-4 in mouse peritoneal macrophages.
Interleukin-4 (IL-4) is an anti-inflammatory cytokine which inhibits many inducible macrophage functions. The present study demonstrates that the ability of IL-4 to inhibit interferon gamma (IFNgamma)-dependent gene transcription is dependent upon STAT6. IL-4 suppressed IFNgamma-induced expression of the MIG (monokine induced by IFNgamma) gene, a C-X-C chemokine, in mouse macrophages. IFNgamma-induced expression of MIG mRNA was abolished in peritoneal macrophages from Stat1-/- mice, and the suppression of MIG mRNA by IL-4 was abolished in macrophages from Stat6-/- mice. Transient transfection assays using a reporter gene containing the MIG gene promoter or the IFNgamma-responsive element (gammaRE) from the MIG gene revealed that the IFNgamma-dependent transcription was suppressed by IL-4, although IL-4 alone had no transactivating function. IFNgamma and IL-4 activated STAT1 and STAT6, respectively, and both proteins were able to bind the gammaRE motif. Furthermore, STAT6 was associated with the co-activator CREB-binding protein in RAW264.7 cells. These observations indicate that STAT6 is necessary for the IL-4-mediated suppression of IFNgamma-induced, STAT1-dependent transcription and suggest that STAT6 may directly suppress the STAT1-dependent transcription by competing with STAT1 for occupancy of the gammaRE motif and/or by competing with limiting quantities of the transcriptional coactivator.
Ohmori
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Y
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Hamilton
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TA
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics; D017931:DNA Primers; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; D017931:DNA Primers; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma