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• W1969228343 abstract "Abstract Objective There is evidence that interleukin‐4 (IL‐4) plays a major role in the induction of extracellular matrix protein synthesis in fibrotic disease. We therefore examined the effect of IL‐4 on collagen synthesis in primary fibroblasts isolated from normal and TSK/+ mice, which spontaneously develop a scleroderma‐like syndrome characterized by diffuse cutaneous hyperplasia. Methods Expression of the IL‐4 receptor was determined by flow cytometry and Western blotting. The IL‐4 signal transduction cascade was analyzed by Western blotting. We assessed the role of signal transducer and activator of transcription 6 (STAT‐6) in IL‐4 induction of α2(I) collagen promoter activity and message levels via luciferase reporter assay and real‐time polymerase chain reaction. The activation status of the transcription factors activator protein 1 (AP‐1) and Sp‐1 upon stimulation with IL‐4 in normal and TSK/+ fibroblasts was examined by electrophoretic mobility shift assay. Results Flow cytometry and Western blotting showed that IL‐4 receptor α expression was elevated in TSK/+ fibroblasts compared with normal fibroblasts. After IL‐4 stimulation, janus‐activated kinase 1 (JAK‐1) and JAK‐2 were phosphorylated to a greater degree in TSK/+ fibroblasts than in C57BL/6 fibroblasts. TSK/+ fibroblasts appeared to be hyperresponsive to IL‐4, displaying increased synthesis of α1(I) collagen messenger RNA (mRNA), collagen protein, and activity of a luciferase reporter construct containing the −300 to +54 murine α2(I) collagen promoter. Overexpression of STAT‐6 enhanced this effect, whereas expression of a dominant‐negative STAT‐6 abrogated the ability of IL‐4 to induce α1(I) collagen mRNA in TSK/+ fibroblasts. Moreover, IL‐4 induced increased DNA binding activity of transcription factors that are important for collagen synthesis. Conclusion Our observations indicate that IL‐4 has a profound effect on several factors that have been identified as playing major roles in the regulation of collagen synthesis and suggest that IL‐4 increases the expression of type I collagen through a mechanism involving the activation of transcription factors that bind to and activate collagen promoter." @default.
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• W1969228343 date "2003-08-01" @default.
• W1969228343 modified "2023-10-17" @default.
• W1969228343 title "Molecular mechanisms of interleukin‐4–induced up‐regulation of type I collagen gene expression in murine fibroblasts" @default.
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• W1969228343 doi "https://doi.org/10.1002/art.11089" @default.
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