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Am J Physiol Lung Cell Mol Physiol 286: L877-L885, 2004. First published November 14, 2003; doi:10.1152/ajplung.00275.2003
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Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4

Steven Bozinovski,1 Jessica Jones,1 Sarah-Jane Beavitt,1 Andrew D. Cook,2 John A. Hamilton,2 and Gary P. Anderson1,3

Lung Disease Research Group, Departments of 1Pharmacology and 3Medicine; 2Arthritis and Inflammation Research Center, Department of Medicine, Royal Melbourne Hospital; and Cooperative Research Center for Chronic Inflammatory Diseases, University of Melbourne, Parkville 3010, Victoria, Australia

Submitted 14 August 2003 ; accepted in final form 12 November 2003

The innate immune inflammatory response to lipopolysaccharide (LPS, an endotoxin) is essential for lung host defense against infection by gram-negative bacteria but is also implicated in the pathogenesis of some lung diseases. Studies on genetically altered mice implicate granulocyte-macrophage colony-stimulating factor (GM-CSF) in lung responses to LPS; however, the physiological effects of GM-CSF neutralization are poorly characterized. We performed detailed kinetic and dose-response analyses of the lung inflammation response to LPS in the presence of the specific GM-CSF-neutralizing antibody 22E9. LPS instilled into the lungs of BALB/c mice induced a dose-dependent inflammation comprised of intense neutrophilia, macrophage infiltration and proliferation, TNF-{alpha} and matrix metalloproteinase release, and macrophage inflammatory protein-2 induction. The neutralization of anti-GM-CSF in a dose-dependent fashion suppressed these inflammatory indexes by <=85% when given before or after LPS or after repeat LPS challenges. Here we report for the first time that the physiological expression of Toll-like receptor-4 in lung is reduced by anti-GM-CSF. We observed that lower Toll-like receptor-4 expression correlated with a similar decline in peak TNF-{alpha} levels in response to endotoxin. Consequently, sustained expression of key inflammatory mediators over 24 h was reduced. These data expand the understanding of the contribution of GM-CSF to innate immune responses in lung and suggest that blocking GM-CSF might benefit some lung diseases where LPS has been implicated in etiology.

lipopolysaccharide; neutrophil; monocyte; granulocyte-macrophage colony-stimulating factor; Toll-like receptor-4


Address for reprint requests and other correspondence: G. Anderson, Lung Disease Research Group, Dept. of Pharmacology, Cooperative Research Center for Chronic Inflammatory Diseases, Univ. of Melbourne, Parkville 3010, Victoria, Australia (E-mail: gpa{at}unimelb.edu.au).




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