TNF-α suppressed TGF-β-induced CTGF expression by switching the binding preference of p300 from Smad4 to p65 |
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| Authors: | Fun Yu Chia-Wei Chou Ching-Chow Chen |
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| Institution: | 1. Endoscopy Center China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China;2. The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China;3. Tianjin Key Labotatory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China;1. Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, United States;2. Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States;3. Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States;4. Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, United States;5. Laboratory of Immunoregulation, NIAID/NIH, Bethesda, MD 20892, United States;6. Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, United States |
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| Abstract: | TGF-β regulates diverse biologic effects including cell growth, cell death or apoptosis, cell differentiation, and extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF), induced by TGF-β has been reported to mediate stimulatory action of TGF-β-induced ECM. Although TNF-α was reported to suppress the TGF-β-induced CTGF gene expression, the molecular mechanism is not well clarified. In this study, we found the inhibitory effect of TNF-α on TGF-β-induced CTGF expression in WT but not p65?/? MEF cells. TNF-α neither induced Smad7 expression nor affected TGF-β-induced Smad2 phosphorylation and nuclear translocation. We demonstrated that p300 physically associated with p65 rather than Smad4 in the presence of both TNF-α and TGF-β. Moreover, the TGF-β-induced binding of p300 and acetylated H4, but not Smad4 to the CTGF promoter was disturbed by TNF-α treatment. Overall, our data showed that suppression of TNF-α on TGF-β-induced CTGF expression is due to the competition of p300 by p65 and Smad4. |
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