title: TLR4 activation induces IL-1β release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung.
abstract: BACKGROUND
  The IL-1 family of cytokines is known to play an important role in inflammation therefore understanding the mechanism by which they are produced is paramount. Despite the recent plethora of publications dedicated to the study of these cytokines, the mechanism by which they are produced in the airway following endotoxin, Lipopolysaccharide (LPS), exposure is currently unclear. The aim was to determine the mechanism by which the IL-1 cytokines are produced after LPS inhaled challenge.
  
  
  METHODS
  Mice were challenged with aerosolised LPS, and lung tissue and bronchiolar lavage fluid (BALF) collected. Targets were measured at the mRNA and protein level; caspase activity was determined using specific assays.
  
  
  RESULTS
  BALF IL-1b/IL-18, but not IL-1a, was dependent on Ice Protease-Activating Factor (IPAF), and to a lesser extent Apoptosis-associated Speck-like protein containing a CARD (ASC). Interestingly, although we measured an increase in mRNA expression for caspase 1 and 11, we could not detect an increase in lung enzyme activity or a role for them in IL-1a/b production. Further investigations showed that whilst we could detect an increase in caspase 8 activity at later points in the time course (during resolution of inflammation), it appeared to play no role in the production of IL-1 cytokines in this model system.
  
  
  CONCLUSIONS
  TLR4 activation increases levels of BALF IL-1b/IL-18 via an IPAF dependent and caspase 1/11/8 independent pathway. Furthermore, it would appear that the presence of IL-1a in the BALF is independent of these pathways. This novel data sheds light on innate signalling pathways in the lung that control the production of these key inflammatory cytokines.
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. suffwan@hotmail.com.
authors.forename: Suffwan
authors.initials: S
authors.lastname: Eltom
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. maria.belvisi@imperial.ac.uk.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. liang.yew-booth@imperial.ac.uk.
authors.forename: Liang
authors.initials: L
authors.lastname: Yew-Booth
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. b.dekkak@imperial.ac.uk.
authors.forename: Bilel
authors.initials: B
authors.lastname: Dekkak
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. s.maher05@imperial.ac.uk.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. kate.fitzgerald@umassmed.edu.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Dubuis
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. e.dubuis@imperial.ac.uk.
authors.forename: Victoria
authors.initials: V
authors.lastname: Jones
authors.affiliation: University of Massachusetts, Division of Infectious Diseases & Immunology, Worcester, MA, 01605, USA. victoria.jones09@imperial.ac.uk.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. m.birrell@imperial.ac.uk.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000336:Aerosols; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D004731:Endotoxins; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C044101:endotoxin, Escherichia coli; C101136:Casp4 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1
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