Tumor Necrosis Factor α Modulates Airway Smooth Muscle Function via the Autocrine Action of Interferon β

• Published in: The Journal of biological chemistry 2003-12, Vol.278 (50), p.50615-50623
• Main Authors: Tliba, Omar, Tliba, Samira, Da Huang, Chien, Hoffman, Rebecca K., DeLong, Peter, Panettieri, Reynold A., Amrani, Yassine
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Cell Nucleus - metabolism; Cells, Cultured; Chemokine CCL5 - metabolism; DNA - metabolism; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunoblotting; Immunohistochemistry; Inflammation; intercellular adhesion molecule 1; Interferon-beta - metabolism; interferon-regulatory factor-1; janus tyrosine kinase 1; Muscle, Smooth - metabolism; Phosphorylation; Protein Binding; RANTES protein; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Trachea - pathology; Transcription, Genetic; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology; Tyk2 tyrosine kinase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M303680200

Current evidence suggests that tumor necrosis factor α (TNFα) 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, TNFα 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, TNFα stimulated γ-activated site-dependent gene transcription in a time- and concentration-dependent manner. Using neutralizing antibodies to IFNβ and TNFα receptor 1, we show that TNFα-induced secretion of IFNβ mediated γ-activated site-dependent gene expression via activation of TNFα receptor 1. In addition, neutralizing antibody to IFNβ also completely abrogated the activation of interferon stimulation response element-dependent gene transcription induced by TNFα. Secreted IFNβ acted as a negative regulator of TNFα-induced interleukin-6 expression, while IFNβ augmented TNFα-induced RANTES (regulated on activation normal T cell expressed and secreted) secretion but had little effect on TNFα-induced intercellular adhesion molecule-1 expression. Furthermore TNFα, a modest airway smooth muscle mitogen, markedly induced DNA synthesis when cells were treated with neutralizing anti-IFNβ. Together these data show that TNFα, via the autocrine action of IFNβ, differentially regulates the expression of proinflammatory genes and DNA synthesis.