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Published ahead of print on January 18, 2005, doi:10.1164/rccm.200403-406OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 814-822, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200403-406OC

Original Article

Agonists of Toll-like Receptors 2 and 4 Activate Airway Smooth Muscle via Mononuclear Leukocytes

Gavin E. Morris, Moira K. B. Whyte, Gillian F. Martin, Peter J. Jose, Steven K. Dower and Ian Sabroe

Academic Units of Respiratory Medicine and Cell Biology, Division of Genomic Medicine, University of Sheffield, Sheffield; Section of Leukocyte Biology, Biomedical Sciences Division, Faculty of Medicine, Imperial College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Ian Sabroe, Ph.D., Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield, M Floor, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK. E-mail: i.sabroe{at}sheffield.ac.uk

Rationale: Toll-like receptors 2 and 4 (TLR2, TLR4) enable cellular responses to bacterial lipoproteins, LPS, and endogenous mediators of cell damage. They have an established role in the activation of leukocytes, endothelial cells, and some smooth muscle cell types, but their roles in airway smooth muscle are uncertain. Objectives: To determine the roles of TLRs in activation of airway smooth muscle. Methods: Airway smooth muscle cells were cultured with TLR agonists, in the presence or absence of mononuclear leukocytes. Measurements and Main Results: We observed expression of TLR2 and TLR4 mRNAs, which could be upregulated by treatment with proinflammatory cytokines in primary human airway smooth muscle, but no important functional responses to agonists of these TLRs were seen. Coincubation of airway smooth muscle with peripheral blood mononuclear cells, at concentrations as low as 250 mononuclear cells/ml, resulted in a marked cooperative response to TLR stimuli, and synergistic production of cytokines, including chemokines (interleukin [IL-]-8) and IL-6. This cooperative response was greater when monocytes were enriched and was transferable using supernatants from LPS-stimulated peripheral blood mononuclear cells. Activation of cocultures required IL-1 generation from mononuclear cells, and was blocked by IL-1 receptor antagonist, though IL-1 generation alone was not sufficient to account for the magnitude of mononuclear cell–dependent coculture activation. Conclusions: These data indicate that potent amplification of inflammation induced by TLR agonists, such as LPS, may be achieved by cooperativity between airway smooth muscle and leukocytes involved in immune surveillance or inflammation.

Key Words: airway smooth muscle • inflammation • innate immunity • LPS • Toll-like receptor




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