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* Laboratory of Respiratory Biology and
Department of Health and Human Services, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; and
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206
Liver X receptor (LXR) 
and β are members of the nuclear receptor superfamily of ligand-activated transcription factors. Best known for triggering "reverse cholesterol transport" gene programs upon their activation by endogenous oxysterols, LXRs have recently also been implicated in regulation of innate immunity. In this study, we define a role for LXRs in regulation of pulmonary inflammation and host defense and identify the lung and neutrophil as novel in vivo targets for pharmacologic LXR activation. LXR is expressed in murine alveolar macrophages, alveolar epithelial type II cells, and neutrophils. Treatment of mice with TO-901317, a synthetic LXR agonist, reduces influx of neutrophils to the lung triggered by inhaled LPS, intratracheal KC chemokine, and intratracheal Klebsiella pneumoniae and impairs pulmonary host defense against this bacterium. Pharmacologic LXR activation selectively modulates airspace cytokine expression induced by both LPS and K. pneumoniae. Moreover, we report for the first time that LXR activation impairs neutrophil motility and identify inhibition of chemokine-induced RhoA activation as a putative underlying mechanism. Taken together, these data define a novel role for LXR in lung pathophysiology and neutrophil biology and identify pharmacologic activation of LXR as a potential tool for modulation of innate immunity in the lung.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by American Heart Association Grant 0275035N (to M.B.F.), American Lung Association Grant 22442N (to S.J.), and National Institutes of Health Grants 5R01HL061407-08 (to G.S.W.) and 5P01HL68743-04 (to J.A.N.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.
2 K.S. and J.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Michael B. Fessler, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, P.O. Box 12233, Maildrop D2-01, Research Triangle Park, NC 27709. E-mail address: fesslerm{at}niehs.nih.gov or Dr. G. Scott Worthen, Abramson Research Center, 416H, Children’s Hospital of Philadelphia, 3516 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: worthen{at}email.chop.edu
4 Abbreviations used in this paper: LXR, liver X receptor; ABCA1, ATP-binding cassette transporter A1; BALF, bronchoalveolar lavage fluid; BAL, bronchoalveolar lavage; GR, glucocorticoid receptor; LIX, LPS-induced CXC chemokine; MPO, myeloperoxidase; NR, nuclear receptor; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; PMN, polymorphonuclear neutrophil; i.t., intratracheal(ly); SPC, surfactant protein C.
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