title: Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD.
abstract: Cigarette smoke (CS), the primary risk factor of chronic obstructive pulmonary disease (COPD), leads to pulmonary inflammation through interleukin-1 receptor (IL-1R)I signalling, as determined using COPD mouse models. It is unclear whether interleukin (IL)-1α or IL-1β, activated by the Nlrp3/caspase-1 axis, is the predominant ligand for IL-1RI in CS-induced responses. We exposed wild-type mice (treated with anti-IL-1α or anti-IL-1β antibodies), and IL-1RI knockout (KO), Nlrp3 KO and caspase-1 KO mice to CS for 3 days or 4 weeks and evaluated pulmonary inflammation. Additionally, we measured the levels of IL-1α and IL-1β mRNA (in total lung tissue by RT-PCR) and protein (in induced sputum by ELISA) of never-smokers, smokers without COPD and patients with COPD. In CS-exposed mice, pulmonary inflammation was dependent on IL-1RI and could be significantly attenuated by neutralising IL-1α or IL-1β. Interestingly, CS-induced inflammation occurred independently of IL-1β activation by the Nlrp3/caspase-1 axis. In human subjects, IL-1α and IL-1β were significantly increased in total lung tissue and induced sputum of patients with COPD, respectively, compared with never-smokers. These results suggest that not only IL-1β but also IL-1α should be considered as an important mediator in CS-induced inflammation and COPD.
authors.affiliation: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: N S
authors.initials: NS
authors.lastname: Pauwels
authors.forename: K R
authors.initials: KR
authors.lastname: Bracke
authors.forename: L L
authors.initials: LL
authors.lastname: Dupont
authors.forename: G R
authors.initials: GR
authors.lastname: Van Pottelberge
authors.forename: S
authors.initials: S
authors.lastname: Provoost
authors.forename: T
authors.initials: T
authors.lastname: Vanden Berghe
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: B N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: G F
authors.initials: GF
authors.lastname: Joos
authors.forename: G G
authors.initials: GG
authors.lastname: Brusselle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D020170:Caspase 1 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D057134:Antibodies, Neutralizing; D051017:Apoptosis Regulatory Proteins; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; D017472:Receptors, Interleukin-1; D014028:Tobacco Smoke Pollution; D020170:Caspase 1