Document Detail

Toll-like receptor 3 mediates expression of clusterin/apolipoprotein J in vascular smooth muscle cells stimulated with RNA released from necrotic cells.
MedLine Citation:
PMID:  20692254     Owner:  NLM     Status:  MEDLINE    
Clusterin/Apolipoprotein J is a protein that is upregulated in a broad spectrum of diverse pathological processes. The predominant form is a secreted glycoprotein (sCLU) with cytoprotective and anti-inflammatory properties which shows enhanced expression in vascular smooth muscle cells (VSMC) following aortic injury and in atherosclerotic disease. Recent evidence indicates that during atherosclerosis, Toll-like receptors (TLRs) are activated in vascular cells by endogenous ligands. Here, we analyzed whether CLU expression in VSMC is controlled by TLRs, and stimulated by factors associated with or released by necrotic cells. Activation of TLR3 by the synthetic RNA analogue polyinosinic-polycytidylic acid (poly(I:C)) in CRL2018 VSMC and in mice led to induction of CLU mRNA and protein synthesis, respectively. In TLR3-deficient 10A yolk sac cells, induction of CLU by poly(I:C) challenge depended on the ectopic expression of human TLR3. In mice lacking the TLR3-signaling adaptor protein TRIF (TIR-domain-containing adaptor protein inducing IFN-β) CLU induction by poly(I:C) was abrogated. In addition to poly(I:C) CLU gene expression in CRL2018 cells was induced by purified cellular RNA and RNA present in necrotic cell lysate. Our data indicate that cellular RNA following its release from necrotic cells in atherosclerotic lesions can act as an endogenous TLR3 ligand to induce CLU expression in VSMC and in vivo. Thus, they expand the view on TLR2 and TLR4 as known pro-atherosclerotic effectors toward TLR3. Conclusively, TLR3 activation induces expression of cytoprotective and anti-inflammatory CLU by VSMC and mice, to potentially counteract atherosclerotic pathology.
M Baiersdörfer; M Schwarz; K Seehafer; C Lehmann; A Heit; H Wagner; C J Kirschning; C Koch-Brandt
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-05
Journal Detail:
Title:  Experimental cell research     Volume:  316     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-09     Completed Date:  2011-01-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3489-500     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Institute of Pharmacy and Biochemistry, J. Gutenberg-University of Mainz, Mainz, Germany.
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MeSH Terms
Adaptor Proteins, Vesicular Transport / genetics
Cell Extracts / chemistry,  pharmacology*
Cell Line
Chemokine CCL2 / genetics
Chloroquine / pharmacology
Clusterin / blood,  genetics,  metabolism*,  pharmacology
Culture Media, Conditioned / pharmacology
Endocytosis / drug effects
Gene Expression / drug effects,  genetics
Hot Temperature
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular / cytology*
Myocytes, Smooth Muscle / drug effects,  metabolism*
Necrosis / metabolism*
Poly I-C / pharmacology
Protein Denaturation
Proteins / chemistry,  metabolism
RNA / pharmacology*
Toll-Like Receptor 3 / agonists,  genetics,  metabolism*
Toll-Like Receptors / agonists,  genetics
Reg. No./Substance:
0/Adaptor Proteins, Vesicular Transport; 0/Ccl2 protein, rat; 0/Cell Extracts; 0/Chemokine CCL2; 0/Clu protein, mouse; 0/Clu protein, rat; 0/Clusterin; 0/Culture Media, Conditioned; 0/Proteins; 0/TICAM-1 protein, mouse; 0/Toll-Like Receptor 3; 0/Toll-Like Receptors; 24939-03-5/Poly I-C; 54-05-7/Chloroquine; 63231-63-0/RNA

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