HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jindra, P. T. Articles by Reed, E. F. Search for Related Content PubMed PubMed Citation Articles by Jindra, P. T. Articles by Reed, E. F.

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway¹

Peter T. Jindra^*, Yi-Ping Jin^*, Enquire Rozengurt and Elaine F. Reed^2,*

^* Department of Pathology and Laboratory Medicine and Department of Medicine, David Geffen School of Medicine and Molecular Biology Institute, University of California, Los Angeles, CA 90095

Anti-HLA Abs have been shown to contribute to the process of transplant vasculopathy by binding to HLA class I molecules expressed by the endothelial and smooth muscle cells of the graft and transducing intracellular signals that elicit cell proliferation. The aim of this study was to determine the role of mammalian target of rapamycin (mTOR) in HLA class I-induced endothelial cell proliferation and to explore in depth the relationship between mTOR complexes and their downstream targets following ligation of HLA class I molecules by anti-HLA Abs. We used small interfering RNA technology to abrogate mTOR, rapamycin-insensitive companion of mTOR (rictor), or regulatory associated protein of mTOR (raptor) to study the function of these gene products to activate proteins involved in MHC class I-induced cell proliferation and survival. Knockdown of mTOR inhibited class I-mediated phosphorylation of proteins downstream of mTOR complex 1 and mTOR complex 2. Furthermore, knockdown of mTOR, rictor, or raptor blocked HLA class I-induced endothelial cell proliferation. Long-term pretreatment with the mTOR inhibitor rapamycin significantly blocked both mTOR-raptor and mTOR-rictor complex formation. Interestingly, rapamycin also blocked class I-induced Akt phosphorylation at Ser⁴⁷³ and Bcl-2 expression. These results support the role of anti-HLA Abs in the process of transplant vasculopathy and suggest that exposure of the graft endothelium to anti-HLA Abs may promote proliferation through the mTOR pathway.

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 National Institute of Allergy and Infectious Diseases Grant R01 AI 42819 and by the American Heart Association Grant-in-Aid 9750894A.

² Address correspondence and reprint requests to Dr. Elaine F. Reed, Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095. E-mail address: ereed{at}mednet.ucla.edu

³ Abbreviations used in this paper: EC, endothelial cell(s); bFGF, basic fibroblast growth factor; 4E-BP1, initiation factor 4E-binding protein 1; FAK, focal adhesion kinase; FGFR, fibroblast growth factor receptor; HAEC, human aortic endothelial cells; mTOR, mammalian target of rapamcyin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; rictor, rapamycin-insensitive companion of TOR; raptor, regulatory associated protein of TOR; S6K, p70 ribosomal S6 kinase; S6RP, S6 ribosomal protein; siRNA, small interfering RNA; Sin1, stress-activated protein kinase-interacting protein 1.