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Published ahead of print on August 17, 2006, doi:10.1165/rcmb.2006-0174OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 36, pp. 114-121, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0174OC

GM-CSF Regulates a PU.1-Dependent Transcriptional Program Determining the Pulmonary Response to LPS

Pierre-Yves Berclaz, Brenna Carey, Marie-Dominique Fillipi, Kara Wernke-Dollries, Nick Geraci, Stephanie Cush, Terry Richardson, Joe Kitzmiller, Michael O'Connor, Christina Hermoyian, Thomas Korfhagen, Jeffrey A. Whitsett and Bruce C. Trapnell

Divisions of Pulmonary Biology and Experimental Hematology, Cincinnati Children's Hospital Medical Center; and University of Cincinnati College of Medicine, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Bruce C. Trapnell, M.D., Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: Bruce.Trapnell{at}chmcc.org

Alveolar macrophages (AMs) normally respond to lipopolysaccharide (LPS) by activating Toll-like receptor (TLR)-4 signaling, a mechanism critical to lung host defense against gram-negative bacteria such as Pseudomonas aeruginosa. Because granulocyte macrophage colony-stimulating factor (GM-CSF)–deficient (GM–/–) mice are hyporesponsive to LPS, we evaluated the role of GM-CSF in TLR-4 signaling in AMs. Pulmonary TNF-{alpha} levels and neutrophil recruitment 4 h after intratracheal administration of Pseudomonas LPS were reduced in GM–/– compared with wild-type (GM+/+) mice. Secretion of TNF-{alpha} by AMs exposed to LPS ex vivo was also reduced in GM–/– mice and restored in mice expressing GM-CSF specifically in the lungs (SPC-GM+/+/GM–/– mice). LPS-dependent NF-{kappa}B promoter activity, TNF-{alpha} secretion, and neutrophil chemokine release were reduced in AM cell lines derived from GM–/– mice (mAM) compared with GM+/+ (MH-S). Retroviral expression of PU.1 in mAM cells, which normally lack PU.1, rescued all of these AM defects. To determine whether GM-CSF, via PU.1, regulated expression of TLR-4 pathway components, mRNA and protein levels for key components were evaluated in MH-S cells (GM+/+, PU.1Positive), mAM cells (GM–/–, PU.1Negative), and mAMPU.1+ cells (GM–/–, PU.1Positive). Cluster of differentiation antigen-14, radioprotective 105, IL-1 receptor–associated kinase (IRAK)-M mRNA, and protein were dependent upon GM-CSF and restored by expression of PU.1. In contrast, expression of other TLR-4 pathway components (myeloid differentiation-2, TLR-4, IRAK-1, IRAK-2, Toll/IL-1 receptor domain containing adapter protein/MyD88 adaptor-like, myeloid differentiation primary-response protein 88, IRAK-4, TNF receptor–associated factor-6, NF-{kappa}B, inhibitor of NF-{kappa}B kinase) were not GM-CSF or PU.1-dependent. These results show that GM-CSF, via PU.1, enables AM responses to P. aeruginosa LPS by regulating expression of a specific subset of components of the TLR-4 signaling pathway.

Key Words: alveolar macrophages • inflammation • lung • neutrophils


CLINICAL RELEVANCE

This study demonstrates that GM-CSF, via PU.1, enables the alveolar macrophage response to Pseudomonas LPS by stimulating expression of a specific subset of components of the Toll-like receptor 4 signaling pathway (CD14, IRAK-M, RP105).

 



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