期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 50, 页码 50615-50623出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M303680200
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资金
- NHLBI NIH HHS [1P50-HL67663, R01 HL055301, 2R01-HL55301, P50 HL067663] Funding Source: Medline
Current evidence suggests that tumor necrosis factor alpha ( TNF alpha) and the family of interferons ( IFNs) synergistically regulate many cellular responses that are believed to be critical in chronic inflammatory diseases, although the underlying mechanisms of such interaction are complex, cell- specific, and not completely understood. In this study, TNF alpha in a time- dependent manner activated both janus tyrosine kinase 1 and Tyk2 tyrosine kinase and increased the nuclear translocation of interferon- regulatory factor- 1, STAT1, and STAT2 in human airway smooth muscle cells. In cells transfected with a luciferase reporter, TNF alpha stimulated gamma- activated site- dependent gene transcription in a time- and concentration- dependent manner. Using neutralizing antibodies to IFNbeta and TNFalpha receptor 1, we show that TNF alpha- induced secretion of IFN beta mediated gamma- activated site- dependent gene expression via activation of TNF alpha receptor 1. In addition, neutralizing antibody to IFN beta also completely abrogated the activation of interferon stimulation response element-dependent gene transcription induced by TNFalpha. Secreted IFN beta acted as a negative regulator of TNF alpha-induced interleukin- 6 expression, while IFN beta augmented TNF alpha- induced RANTES ( regulated on activation normal T cell expressed and secreted) secretion but had little effect on TNF alpha- induced intercellular adhesion molecule- 1 expression. Furthermore TNFalpha, a modest airway smooth muscle mitogen, markedly induced DNA synthesis when cells were treated with neutralizing anti-IFNbeta. Together these data show that TNFalpha, via the autocrine action of IFN beta, differentially regulates the expression of proinflammatory genes and DNA synthesis.
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