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Divisions of
*
Pediatric Critical Care and
Pediatric Infectious Diseases, Steven Spielberg Pediatric Research Center Cedars-Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90048; and
Department of Microbiology, Montana State University, Bozeman, MT 59717
Active inflammation and NF-
B activation contribute fundamentally
to atherogenesis and plaque disruption. Accumulating evidence has
implicated specific infectious agents including
Chlamydia pneumoniae in the progression
of atherogenesis. Chlamydial heat shock protein 60 (cHSP60) has been
implicated in the induction of deleterious immune responses in human
chlamydial infections and has been found to colocalize with
infiltrating macrophages in atheroma lesions. cHSP60 might stimulate,
enhance, and maintain innate immune and inflammatory responses and
contribute to atherogenesis. In this study, we investigated the
signaling mechanism of cHSP60. Recombinant cHSP60 rapidly activated
NF-B in human microvascular endothelial cells (EC) and in mouse
macrophages, and induced human IL-8 promoter activity in EC. The
inflammatory effect of cHSP60 was heat labile, thus excluding a role of
contaminating LPS, and was blocked by specific anti-chlamydial
HSP60 mAb. In human vascular EC which express Toll-like receptor 4
(TLR4) mRNA and protein, nonsignaling TLR4 constructs that act as
dominant negative blocked cHSP60-mediated NF-B activation.
Furthermore, an anti-TLR4 Ab abolished cHSP60-induced cellular
activation, whereas a control Ab had no effect. In 293 cells,
cHSP60-mediated NF-B activation required both TLR4 and MD2. A
dominant-negative MyD88 construct also inhibited cHSP60-induced NF-B
activation. Collectively, our results indicate that cHSP60 is a potent
inducer of vascular EC and macrophage inflammatory responses, which are
very relevant to atherogenesis. The inflammatory effects are mediated
through the innate immune receptor complex TLR4-MD2 and proceeds via
the MyD88-dependent signaling pathway. These findings may help
elucidate the mechanisms by which chronic asymptomatic chlamydial
infection contribute to atherogenesis.
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B. Opitz, S. Forster, A. C. Hocke, M. Maass, B. Schmeck, S. Hippenstiel, N. Suttorp, and M. Krull Nod1-Mediated Endothelial Cell Activation by Chlamydophila pneumoniae Circ. Res., February 18, 2005; 96(3): 319 - 326. [Abstract] [Full Text] [PDF]
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B. J. Johnson, T. T. T. Le, C. A. Dobbin, T. Banovic, C. B. Howard, F. d. M. L. Flores, D. Vanags, D. J. Naylor, G. R. Hill, and A. Suhrbier Heat Shock Protein 10 Inhibits Lipopolysaccharide-induced Inflammatory Mediator Production J. Biol. Chem., February 11, 2005; 280(6): 4037 - 4047. [Abstract] [Full Text] [PDF]
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 T. Hirata, Y. Osuga, Y. Hirota, K. Koga, O. Yoshino, M. Harada, C. Morimoto, T. Yano, O. Nishii, O. Tsutsumi, et al. Evidence for the Presence of Toll-Like Receptor 4 System in the Human Endometrium J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 548 - 556. [Abstract] [Full Text] [PDF]
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I. H Haralambieva, I. D Iankov, P. V Ivanova, V. Mitev, and I. G Mitov Chlamydophila pneumoniae induces p44/p42 mitogen-activated protein kinase activation in human fibroblasts through Toll-like receptor 4 J. Med. Microbiol., December 1, 2004; 53(12): 1187 - 1193. [Abstract] [Full Text] [PDF]
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L. L. Stoll, G. M. Denning, and N. L. Weintraub Potential Role of Endotoxin as a Proinflammatory Mediator of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2227 - 2236. [Abstract] [Full Text] [PDF]
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K. S. Michelsen, T. M. Doherty, P. K. Shah, and M. Arditi TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis J. Immunol., November 15, 2004; 173(10): 5901 - 5907. [Abstract] [Full Text] [PDF]
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A. A. R. Tobian, D. H. Canaday, and C. V. Harding Bacterial Heat Shock Proteins Enhance Class II MHC Antigen Processing and Presentation of Chaperoned Peptides to CD4+ T Cells J. Immunol., October 15, 2004; 173(8): 5130 - 5137. [Abstract] [Full Text] [PDF]
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 R Arroyo-Espliguero, P Avanzas, S Jeffery, and J C Kaski CD14 and toll-like receptor 4: a link between infection and acute coronary events? Heart, September 1, 2004; 90(9): 983 - 988. [Abstract] [Full Text] [PDF]
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M.-F. Tsan and B. Gao Endogenous ligands of Toll-like receptors J. Leukoc. Biol., September 1, 2004; 76(3): 514 - 519. [Abstract] [Full Text] [PDF]
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J. A. Whitsett, C. J. Bachurski, K. C. Barnes, P. A. Bunn Jr., L. M. Case, D. N. Cook, D. Crooks, M. W. Duncan, L. Dwyer-Nield, R. C. Elston, et al. Functional Genomics of Lung Disease Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2/S1): S1 - S81. [Full Text] [PDF]
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 R. Mahanonda, N. Sa-Ard-Iam, O. Charatkulangkun, A. Promsudthi, R.E. Schifferle, K. Yongvanichit, and S. Pichyangkul Monocyte Activation by Porphyromonas gingivalis LPS in Aggressive Periodontitis with the Use of Whole-blood Cultures Journal of Dental Research, July 1, 2004; 83(7): 540 - 545. [Abstract] [Full Text] [PDF]
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A. G. Rothfuchs, C. Trumstedt, H. Wigzell, and M. E. Rottenberg Intracellular Bacterial Infection-Induced IFN-{gamma} Is Critically but Not Solely Dependent on Toll-Like Receptor 4-Myeloid Differentiation Factor 88-IFN-{alpha}{beta}-STAT1 Signaling J. Immunol., May 15, 2004; 172(10): 6345 - 6353. [Abstract] [Full Text] [PDF]
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W.-F. Lo, C. D. Dunn, H. Ong, E. S. Metcalf, and M. J. Soloski Bacterial and Host Factors Involved in the Major Histocompatibility Complex Class Ib-Restricted Presentation of Salmonella Hsp 60: Novel Pathway Infect. Immun., May 1, 2004; 72(5): 2843 - 2849. [Abstract] [Full Text] [PDF]
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A. A. R. Tobian, D. H. Canaday, W. H. Boom, and C. V. Harding Bacterial Heat Shock Proteins Promote CD91-Dependent Class I MHC Cross-Presentation of Chaperoned Peptide to CD8+ T Cells by Cytosolic Mechanisms in Dendritic Cells versus Vacuolar Mechanisms in Macrophages J. Immunol., May 1, 2004; 172(9): 5277 - 5286. [Abstract] [Full Text] [PDF]
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 M.-F. Tsan and B. Gao Cytokine function of heat shock proteins Am J Physiol Cell Physiol, April 1, 2004; 286(4): C739 - C744. [Abstract] [Full Text] [PDF]
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C. Monaco and E. Paleolog Nuclear factor {kappa}B: a potential therapeutic target in atherosclerosis and thrombosis Cardiovasc Res, March 1, 2004; 61(4): 671 - 682. [Abstract] [Full Text] [PDF]
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A. B. Lichtenwalner, D. L. Patton, W. C. Van Voorhis, Y. T. C. Sweeney, and C.-C. Kuo Heat Shock Protein 60 Is the Major Antigen Which Stimulates Delayed-Type Hypersensitivity Reaction in the Macaque Model of Chlamydia trachomatis Salpingitis Infect. Immun., February 1, 2004; 72(2): 1159 - 1161. [Abstract] [Full Text] [PDF]
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K. Chen, J. Lu, L. Wang, and Y.-H. Gan Mycobacterial heat shock protein 65 enhances antigen cross-presentation in dendritic cells independent of Toll-like receptor 4 signaling J. Leukoc. Biol., February 1, 2004; 75(2): 260 - 266. [Abstract] [Full Text] [PDF]
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A. P. Gobert, J.-C. Bambou, C. Werts, V. Balloy, M. Chignard, A. P. Moran, and R. L. Ferrero Helicobacter pylori Heat Shock Protein 60 Mediates Interleukin-6 Production by Macrophages via a Toll-like Receptor (TLR)-2-, TLR-4-, and Myeloid Differentiation Factor 88-independent Mechanism J. Biol. Chem., January 2, 2004; 279(1): 245 - 250. [Abstract] [Full Text] [PDF]
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S. R. Coats, R. A. Reife, B. W. Bainbridge, T.-T. T. Pham, and R. P. Darveau Porphyromonas gingivalis Lipopolysaccharide Antagonizes Escherichia coli Lipopolysaccharide at Toll-Like Receptor 4 in Human Endothelial Cells Infect. Immun., December 1, 2003; 71(12): 6799 - 6807. [Abstract] [Full Text] [PDF]
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T. Darville, J. M. O'Neill, C. W. Andrews Jr., U. M. Nagarajan, L. Stahl, and D. M. Ojcius Toll-Like Receptor-2, but Not Toll-Like Receptor-4, Is Essential for Development of Oviduct Pathology in Chlamydial Genital Tract Infection J. Immunol., December 1, 2003; 171(11): 6187 - 6197. [Abstract] [Full Text] [PDF]
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F. Re and J. L. Strominger Separate Functional Domains of Human MD-2 Mediate Toll-Like Receptor 4-Binding and Lipopolysaccharide Responsiveness J. Immunol., November 15, 2003; 171(10): 5272 - 5276. [Abstract] [Full Text] [PDF]
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 E. S. Van Amersfoort, T. J. C. Van Berkel, and J. Kuiper Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock Clin. Microbiol. Rev., July 1, 2003; 16(3): 379 - 414. [Abstract] [Full Text] [PDF]
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B. Gao and M.-F. Tsan Recombinant Human Heat Shock Protein 60 Does Not Induce the Release of Tumor Necrosis Factor {alpha} from Murine Macrophages J. Biol. Chem., June 13, 2003; 278(25): 22523 - 22529. [Abstract] [Full Text] [PDF]
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O. Equils, M. L. Schito, H. Karahashi, Z. Madak, A. Yarali, K. S. Michelsen, A. Sher, and M. Arditi Toll-Like Receptor 2 (TLR2) and TLR9 Signaling Results in HIV-Long Terminal Repeat Trans-Activation and HIV Replication in HIV-1 Transgenic Mouse Spleen Cells: Implications of Simultaneous Activation of TLRs on HIV Replication J. Immunol., May 15, 2003; 170(10): 5159 - 5164. [Abstract] [Full Text] [PDF]
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F. Bea, M. H. Puolakkainen, T. McMillen, F. N. Hudson, N. Mackman, C. C. Kuo, L. A. Campbell, and M. E. Rosenfeld Chlamydia pneumoniae Induces Tissue Factor Expression in Mouse Macrophages via Activation of Egr-1 and the MEK-ERK1/2 Pathway Circ. Res., March 7, 2003; 92(4): 394 - 401. [Abstract] [Full Text] [PDF]
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B. Gao and M.-F. Tsan Endotoxin Contamination in Recombinant Human Heat Shock Protein 70 (Hsp70) Preparation Is Responsible for the Induction of Tumor Necrosis Factor alpha Release by Murine Macrophages J. Biol. Chem., January 3, 2003; 278(1): 174 - 179. [Abstract] [Full Text] [PDF]
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 W van Eden, R van der Zee, P van Kooten, S E Berlo, P M Cobelens, A Kavelaars, C J Heijnen, B Prakken, S Roord, and S Albani Balancing the immune system: Th1 and Th2 Ann Rheum Dis, November 1, 2002; 61(90002): ii25 - 28. [Full Text] [PDF]
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Q. Xu Role of Heat Shock Proteins in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1547 - 1559. [Abstract] [Full Text] [PDF]
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