title: Cigarette smoke activates human monocytes by an oxidant-AP-1 signaling pathway: implications for steroid resistance.
abstract: Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smoking-induced pathophysiology is often resistant to the anti-inflammatory effects of glucocorticoids. The nature of cigarette smoke-induced inflammation is still not defined, although neutrophil recruitment and activation seem to be consistent features. In the current study, we have used a range of approaches to demonstrate that cigarette smoke activates human monocytes and macrophages to release the CXC chemokine CXCL8 [(interleukin-8 (IL-8)]. Furthermore, we show for the first time that cigarette smoke synergizes with proinflammatory cytokines IL-1beta and tumor necrosis factor-alpha, and it is this interaction that confers steroid resistance to smoke-induced CXCL8 release. We go on to show that smoke-induced activation of human cells is an oxidant-mediated phenomenon acting through activator protein-1, but not nuclear factor kappaB, pathway. These observations add significantly to our understanding of smoke as an inflammatory stimulus that has implications for potential the development of treatments of smoking or related disease.
authors.affiliation: Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Imperial College London, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walters
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Paul-Clark
authors.forename: Shaun K
authors.initials: SK
authors.lastname: McMaster
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007375:Interleukin-1 / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D009000:Monocytes / Q000502:physiology*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects*; D018808:Transcription Factor AP-1 / Q000502:physiology*
chemical_list: D019743:Chemokines, CXC; D005938:Glucocorticoids; D007375:Interleukin-1; D012333:RNA, Messenger; D018808:Transcription Factor AP-1