Department of Medicine, Division of Infectious Disease & Immunology
Genomics | Immunopathology | Respiratory Tract Diseases
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.
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Citation: Respir Res. 2014 Aug 2;15(1):87. Link to article on publisher's site
DOI of Published Version
Eltom, Suffwan; Belvisi, Maria G.; Yew-Booth, Liang; Dekkak, Bilel; Maher, Sarah A.; Dubuis, Eric D.; Jones, Victoria; Fitzgerald, Kate A.; and Birrell, Mark A., "TLR4 activation induces IL-1ss release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung" (2014). Open Access Articles. 2420.
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