title: Nitric oxide suppresses LPS-induced inflammation in a mouse asthma model by attenuating the interaction of IKK and Hsp90.
abstract: A feature of allergic airway disease is the observed increase of nitric oxide (NO) in exhaled breath. Gram-negative bacterial infections have also been linked with asthma exacerbations. However, the role of NO in asthma exacerbations with gram-negative bacterial infections is still unclear. In this study, we examined the role of NO in lipopolysaccharide (LPS)-induced inflammation in an ovalbumin (OVA)-challenged mouse asthma model. To determine whether NO affected the LPS-induced response, a NO donor (S-nitroso-N-acetylpenicillamine, SNAP) or a selective inhibitor of NO synthase (1400W) was injected intraperitoneally into the mice before the LPS stimulation. Decreased levels of proinflammatory cytokines were demonstrated in the bronchoalveolar lavage fluid from mice treated with SNAP, whereas increased levels of cytokines were found in the 1400W-treated mice. To further explore the molecular mechanism of NO-mediated inhibition of proinflammatory responses in macrophages, RAW 264.7 cells were treated with 1400W or SNAP before LPS stimulation. LPS-induced inflammation in the cells was attenuated by the presence of NO. The LPS-induced IκB kinase (IKK) activation and the expression of IKK were reduced by NO through attenuation of the interaction between Hsp90 and IKK in the cells. The IKK decrease in the lung immunohistopathology was verified in SNAP-treated asthma mice, whereas IKK increased in the 1400W-treated group. We report for the first time that NO attenuates the interaction between Hsp90 and IKK, decreasing the stability of IKK and causing the down-regulation of the proinflammatory response. Furthermore, the results suggest that NO may repress LPS-stimulated innate immunity to promote pulmonary bacterial infection in asthma patients.
authors.affiliation: Institute of Bioscience and Biotechnology, Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan, Republic of China Department of Pediatrics, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Ming-Yung
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan, Republic of China Department of Education and Research, Taipei City Hospital, Taipei 100, Taiwan.
authors.forename: Kuang-Hui
authors.initials: KH
authors.lastname: Sun
authors.affiliation: Department of Dermatology, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Chiang
authors.affiliation: Department of Pediatrics, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Huang
authors.affiliation: Division of Urology, Department of Surgery, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Guang-Huan
authors.initials: GH
authors.lastname: Sun
authors.affiliation: Institute of Bioscience and Biotechnology, Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan, Republic of China.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Tsou
authors.affiliation: Division of Urology, Department of Surgery, Taoyuan Armed Forces General Hospital 32551, Taiwan, Republic of China.
authors.forename: Huan-Yun
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Institute of Bioscience and Biotechnology, Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan, Republic of China tsj@mail.ntou.edu.tw.
authors.forename: Shye-Jye
authors.initials: SJ
authors.lastname: Tang
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D051550:I-kappa B Kinase / Q000502:physiology*; D007097:Imines / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000494:pharmacology* / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010047:Ovalbumin / Q000009:adverse effects; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; D007097:Imines; D008070:Lipopolysaccharides; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D010047:Ovalbumin; D019001:Nitric Oxide Synthase; D051550:I-kappa B Kinase
keywords: IκB kinase; Nitric oxide; asthma; heat shock protein 90; nuclear factor κB