STAT6 mediates eotaxin-1 expression in IL-4 or TNF-alpha-induced fibroblasts.
Eosinophils are attracted to sites of allergic inflammation by a number of chemoattractants including eotaxin-1. This chemokine can be secreted from epithelial cells and fibroblasts after IL-4 and TNF-alpha stimulation in a synergistic fashion. TNF-alpha activated gene expression at the transcriptional level in a STAT6-dependent manner, because: 1) eotaxin-1 promoter luciferase constructs were TNF-alpha inducible in STAT6-defective HEK293 cells only on cotransfection of STAT6 expression vector, an effect that was partially mediated by activation-induced binding of NF-kappa B proteins to a composite STAT6/NF-kappa B element; 2) reporter constructs defective in STAT6 DNA binding did not respond to TNF-alpha stimulation; 3) eotaxin-1 protein secretion was detected only in STAT6-transfected HEK293 cell supernatants on TNF-alpha treatment; and 4) a trans-dominant negative STAT6 protein inhibited TNF-alpha-induced eotaxin-1 secretion in primary fibroblasts. TNF-alpha inducibility of the IL-8 and monocyte chemoattractant protein-1 genes was not dependent on STAT6 expression in the same experimental systems. The inducing effect of IL-4 and IL-13 was also mediated by STAT6. The synergistic effect of IL-4 and TNF-alpha observed at the RNA and the protein level was not seen at the promoter level. The data demonstrate that both IL-4 and TNF-alpha induce eotaxin-1 expression at the level of transcription via a STAT6-mediated pathway.
Department of Allergic Diseases, Novartis Research Institute, Vienna, Austria.
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Woisetschläger
D000328:Adult; D002460:Cell Line; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D015847:Interleukin-4 / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D004247:DNA