This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Maitra, U.
Right arrow Articles by Li, L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maitra, U.
Right arrow Articles by Li, L.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2009, p. 5989-5997, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00541-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

An Innate Immunity Signaling Process Suppresses Macrophage ABCA1 Expression through IRAK-1-Mediated Downregulation of Retinoic Acid Receptor {alpha} and NFATc2 {triangledown} ,{dagger}

Urmila Maitra,1 John S. Parks,2 and Liwu Li1*

Laboratory of Innate Immunity and Inflammation, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061,1 Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 271572

Received 24 April 2009/ Returned for modification 9 June 2009/ Accepted 8 September 2009

ATP-binding cassette transporter A1 (ABCA1) plays a central role in promoting cholesterol efflux from macrophages, thereby reducing the risk of foam cell formation and atherosclerosis. The expression of ABCA1 is induced by members of the nuclear receptor family of transcription factors, including retinoic acid receptors (RARs). A key innate immunity signaling kinase, IRAK-1, has been associated with an increased risk of atherosclerosis in humans and mice. This prompted us to investigate the potential connection between IRAK-1 and the expression of ABCA1. Here, we demonstrate that nuclear RAR{alpha} levels are dramatically elevated in IRAK-1–/– macrophages. Correspondingly, IRAK-1–/– macrophages exhibit increased expression of ABCA1 mRNA and protein, as well as elevated cholesterol efflux in response to the RAR ligand ATRA. Analysis of the ABCA1 proximal promoter revealed binding sites for both RAR and NFAT. Chromatin immunoprecipitation assays demonstrated increased binding of RAR{alpha} and NFATc2 to the ABCA1 promoter in IRAK-1–/– macrophages compared to wild-type macrophages. Additionally, lipopolysaccharide pretreatment reduced the nuclear levels of RAR{alpha} and decreased ABCA1 expression and cholesterol efflux in wild-type but not in IRAK-1–/– cells. In summary, this study reveals a novel connection between innate immunity signaling processes and the regulation of ABCA1 expression in macrophages and defines a potential therapeutic target for treating atherosclerosis.

* Corresponding author. Mailing address: Life Science 1 Building, Washington Street, Department of Biology, Virginia Tech, Blacksburg, VA 24061. Phone: (540) 231-1433. Fax: (540) 231-4043. E-mail: lwli{at}vt.edu

{triangledown} Published ahead of print on 14 September 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2009, p. 5989-5997, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00541-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»