Noxa/HSP27 complex delays degradation of ubiquitylated IkBα in airway epithelial cells to reduce pulmonary inflammation
| Autor: | Jialing Xiang, Yohannes A. Mebratu, J.T. Jones, Chunyu Zhang, Yohannes Tesfaigzi, Christopher M. Evans, Marc G. Wathelet, Hitendra S. Chand, Burton F. Dickey |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Transgene medicine.medical_treatment Immunology HSP27 Heat-Shock Proteins Inflammation Mice Transgenic Respiratory Mucosa Article 03 medical and health sciences Interferon-gamma Mice 0302 clinical medicine Hsp27 Ubiquitin NF-KappaB Inhibitor alpha hemic and lymphatic diseases medicine Hypersensitivity Immunology and Allergy Animals Humans Antigens Dermatophagoides Mice Knockout biology Chemistry Pyroglyphidae Ubiquitination Pneumonia 3. Good health Cell biology Mice Inbred C57BL IκBα Disease Models Animal 030104 developmental biology Cytokine Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Proteolysis biology.protein Phosphorylation medicine.symptom |
| Zdroj: | Mucosal immunology |
| ISSN: | 1935-3456 |
| Popis: | IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa-/- compared with noxa+/+ mice. Noxa expression blocked transforming necrosis factor alpha (TNF-α)-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα, blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects. |
| Databáze: | OpenAIRE |
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