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From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular
Division (A.K., G.K.S., P.L.), and the Immunology Research Division,
Department of Pathology (A.H.L.), Brigham and Women's Hospital, Harvard
Medical School, Boston, Mass.
Correspondence to Peter Libby, MD, Cardiovascular Division, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Background—Recent evidence has
implicated Chlamydia pneumoniae in the aggravation of
atherosclerosis. However, the mechanisms by which this
agent affects atherogenesis remain poorly understood. Chlamydiae
produce large amounts of heat shock protein 60 (HSP 60) during chronic,
persistent infections, and C pneumoniae localizes
predominantly within plaque macrophages. Several studies have
furnished evidence that endogenous (human) HSP 60 may play
a role in atherogenesis. We tested here the hypothesis that
atheroma contains chlamydial HSP 60 and that this bacterial
product might stimulate macrophage functions considered
relevant to atherosclerosis and its complications, such
as production of proinflammatory cytokines as tissue
necrosis factor-
Methods and Results—Surgical specimens of human carotid
atherosclerotic arteries (n=19) and normal arterial wall
samples (n=7, 2 carotid arteries and 5 aortas) were tested
immunohistochemically for the presence of chlamydial HSP 60 and human
HSP 60. Macrophage localization of these antigens was assessed
by double immunostaining. Murine peritoneal
macrophages, maintained in serum-free conditions for 48 hours
after harvesting, were incubated with C pneumoniae,
chlamydial HSP 60, human HSP 60, or Escherichia coli
lipopolysaccharide (LPS). Culture supernatants, collected at 24
hours for concentration-dependence experiments and at up to 72 hours
for time-dependence experiments, were analyzed for TNF-
Conclusions—Chlamydial HSP 60 frequently colocalizes with human
HSP 60 in plaque macrophages in human atherosclerotic lesions.
Chlamydial and human HSP 60 induce TNF-
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Chlamydial Heat Shock Protein 60 Localizes in Human Atheroma and Regulates Macrophage Tumor Necrosis Factor-
and Matrix Metalloproteinase Expression
(TNF-) and matrix-degrading
metalloproteinases (MMPs). by
ELISA and for MMP by gelatin zymography. Atherosclerotic lesions showed
immunoreactive chlamydial HSP 60 in 47% (9 of 19) of the cases and
human HSP 60 in 89% (17 of 19) of the cases. Chlamydial HSP 60
colocalized with human HSP 60 within plaque macrophages in 77%
(7 of 9) of the cases. Nonatherosclerotic samples contained neither
HSP. Both C pneumoniae and recombinant chlamydial HSP 60
induced TNF- production by mouse macrophages in a
concentration- and time-dependent fashion. E coli LPS
and human HSP 60 produced similar effects. Similarly, C
pneumoniae and HSPs induced MMPs in a concentration- and
time-dependent manner. Heat treatment abolished the effect of C
pneumoniae and HSPs on both TNF- and MMP production,
but it did not alter the ability of E coli LPS to induce
these functions. and MMP production
by macrophages. Chlamydial HSP 60 might mediate the induction
of these effects by C pneumoniae. Induction of such
macrophage functions provides potential mechanisms by which
chlamydial infections may promote atherogenesis and precipitate acute
ischemic events.
Key Words: proteins • ischemia • atherosclerosis
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|
|
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 |
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|
|
|
|
|
|
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|
|
|
|
 |
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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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]
|
|
|
|
|
|
M. Benagiano, A. Azzurri, A. Ciervo, A. Amedei, C. Tamburini, M. Ferrari, J. L. Telford, C. T. Baldari, S. Romagnani, A. Cassone, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions PNAS, May 27, 2003; 100(11): 6658 - 6663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Huittinen, M. Leinonen, L. Tenkanen, H. Virkkunen, M. Manttari, T. Palosuo, V. Manninen, and P. Saikku Synergistic Effect of Persistent Chlamydia pneumoniae Infection, Autoimmunity, and Inflammation on Coronary Risk Circulation, May 27, 2003; 107(20): 2566 - 2570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O Ishida, H Oku, T Ikeda, M Nishimura, K Kawagoe, and K Nakamura Is Chlamydia pneumoniae infection a risk factor for age related macular degeneration? Br. J. Ophthalmol., May 1, 2003; 87(5): 523 - 524. [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Kalayoglu, C. Galvan, O. S. Mahdi, G. I. Byrne, and S. Mansour Serological Association Between Chlamydia pneumoniae Infection and Age-Related Macular Degeneration Arch Ophthalmol, April 1, 2003; 121(4): 478 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. J. Angiolillo, G. Liuzzo, S. Pelliccioni, E. De Candia, R. Landolfi, F. Crea, A. Maseri, and L. M. Biasucci Combined role of the Lewis antigenic system, Chlamydia pneumoniae, and C-reactive protein in unstable angina J. Am. Coll. Cardiol., February 19, 2003; 41(4): 546 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yang, W. C. Hooper, D. J. Phillips, M. L. Tondella, and D. F. Talkington Induction of Proinflammatory Cytokines in Human Lung Epithelial Cells during Chlamydia pneumoniae Infection Infect. Immun., February 1, 2003; 71(2): 614 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. V. Kalayoglu, P. Libby, and G. I. Byrne Chlamydia pneumoniae as an Emerging Risk Factor in Cardiovascular Disease JAMA, December 4, 2002; 288(21): 2724 - 2731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Forrester Prevention of Plaque Rupture: A New Paradigm of Therapy Ann Intern Med, November 19, 2002; 137(10): 823 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Dong and P. J. Goldschmidt-Clermont E2F1: A Magic Bullet for Atherosclerosis? Circulation, November 19, 2002; 106(21): 2640 - 2641. [Full Text] [PDF]
|
|
|
|
 |
|
 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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|
|
|
|
 |
|
 F Blasi, S Damato, R Cosentini, P Tarsia, R Raccanelli, S Centanni, and L Allegra Chlamydia pneumoniae and chronic bronchitis: association with severity and bacterial clearance following treatment Thorax, August 1, 2002; 57(8): 672 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Prasad, J. Zhu, J. P.J. Halcox, M. A. Waclawiw, S. E. Epstein, and A. A. Quyyumi Predisposition to Atherosclerosis by Infections: Role of Endothelial Dysfunction Circulation, July 9, 2002; 106(2): 184 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 I. W. FONG Infections and their role in atherosclerotic vascular disease J Am Dent Assoc, June 1, 2002; 133(suppl_1): 7S - 13S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
|