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
BackgroundRecent 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 ResultsSurgical 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-
ConclusionsChlamydial 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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G. Caligiuri, M. Rottenberg, A. Nicoletti, H. Wigzell, and G. K. Hansson Chlamydia pneumoniae Infection Does Not Induce or Modify Atherosclerosis in Mice Circulation, June 12, 2001; 103(23): 2834 - 2838. [Abstract] [Full Text] [PDF] |
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T. Huittinen, D. Hahn, T. Anttila, E. Wahlstrom, P. Saikku, and M. Leinonen Host immune response to Chlamydia pneumoniae heat shock protein 60 is associated with asthma Eur. Respir. J., June 1, 2001; 17(6): 1078 - 1082. [Abstract] [Full Text] [PDF] |
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G. Liuzzo, D. J. Angiolillo, A. Buffon, V. Rizzello, C. Colizzi, F. Ginnetti, L. M. Biasucci, and A. Maseri Enhanced Response of Blood Monocytes to In Vitro Lipopolysaccharide-Challenge in Patients With Recurrent Unstable Angina Circulation, May 8, 2001; 103(18): 2236 - 2241. [Abstract] [Full Text] [PDF] |
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K. Aalto-Setala, K. Laitinen, L. Erkkila, M. Leinonen, M. Jauhiainen, C. Ehnholm, M. Tamminen, M. Puolakkainen, I. Penttila, and P. Saikku Chlamydia pneumoniae Does Not Increase Atherosclerosis in the Aortic Root of Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2001; 21(4): 578 - 584. [Abstract] [Full Text] [PDF] |
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R. LaBiche, D. Koziol, T. C. Quinn, C. Gaydos, S. Azhar, G. Ketron, S. Sood, and T. J. DeGraba Presence of Chlamydia pneumoniae in Human Symptomatic and Asymptomatic Carotid Atherosclerotic Plaque Stroke, April 1, 2001; 32(4): 855 - 860. [Abstract] [Full Text] [PDF] |
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B. K. Coombes and J. B. Mahony cDNA Array Analysis of Altered Gene Expression in Human Endothelial Cells in Response to Chlamydia pneumoniae Infection Infect. Immun., March 1, 2001; 69(3): 1420 - 1427. [Abstract] [Full Text] [PDF] |
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P. Vehmaan-Kreula, M. Puolakkainen, M. Sarvas, H. G. Welgus, and P. T. Kovanen Chlamydia pneumoniae Proteins Induce Secretion of the 92-kDa Gelatinase by Human Monocyte- Derived Macrophages Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21 (1): e1 - e8. [Abstract] [Full Text] [PDF] |
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M. Naghavi, Z. Barlas, S. Siadaty, S. Naguib, M. Madjid, and W. Casscells Association of Influenza Vaccination and Reduced Risk of Recurrent Myocardial Infarction Circulation, December 19, 2000; 102(25): 3039 - 3045. [Abstract] [Full Text] [PDF] |
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A Meijer, P J M Roholl, S K Gielis-Proper, and J M Ossewaarde Chlamydia pneumoniae antigens, rather than viable bacteria, persist in atherosclerotic lesions J. Clin. Pathol., December 1, 2000; 53(12): 911 - 916. [Abstract] [Full Text] [PDF] |
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J. T. Grayston Secondary Prevention Antibiotic Treatment Trials for Coronary Artery Disease Circulation, October 10, 2000; 102(15): 1742 - 1743. [Full Text] [PDF] |
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J. B. Muhlestein, J. L. Anderson, J. F. Carlquist, K. Salunkhe, B. D. Horne, R. R. Pearson, T. J. Bunch, A. Allen, S. Trehan, and C. Nielson Randomized Secondary Prevention Trial of Azithromycin in Patients With Coronary Artery Disease : Primary Clinical Results of the ACADEMIC Study Circulation, October 10, 2000; 102(15): 1755 - 1760. [Abstract] [Full Text] [PDF] |
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R. G. Rank, A. K. Bowlin, and K. A. Kelly Characterization of Lymphocyte Response in the Female Genital Tract during Ascending Chlamydial Genital Infection in the Guinea Pig Model Infect. Immun., September 1, 2000; 68(9): 5293 - 5298. [Abstract] [Full Text] [PDF] |
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S A Morre, W Stooker, W K Lagrand, A J C van den Brule, and H W M Niessen Microorganisms in the aetiology of atherosclerosis J. Clin. Pathol., September 1, 2000; 53(9): 647 - 654. [Abstract] [Full Text] [PDF] |
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M. Mayr, S. Kiechl, J. Willeit, G. Wick, and Q. Xu Infections, Immunity, and Atherosclerosis : Associations of Antibodies to Chlamydia pneumoniae, Helicobacter pylori, and Cytomegalovirus With Immune Reactions to Heat-Shock Protein 60 and Carotid or Femoral Atherosclerosis Circulation, August 22, 2000; 102(8): 833 - 839. [Abstract] [Full Text] [PDF] |
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Q. Xu, G. Schett, H. Perschinka, M. Mayr, G. Egger, F. Oberhollenzer, J. Willeit, S. Kiechl, and G. Wick Serum Soluble Heat Shock Protein 60 Is Elevated in Subjects With Atherosclerosis in a General Population Circulation, July 4, 2000; 102(1): 14 - 20. [Abstract] [Full Text] [PDF] |
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I. W. Fong Emerging relations between infectious diseases and coronary artery disease and atherosclerosis Can. Med. Assoc. J., July 1, 2000; 163(1): 49 - 56. [Abstract] [Full Text] [PDF] |
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R. E. Molestina, R. D. Miller, A. B. Lentsch, J. A. Ramirez, and J. T. Summersgill Requirement for NF-kappa B in Transcriptional Activation of Monocyte Chemotactic Protein 1 by Chlamydia pneumoniae in Human Endothelial Cells Infect. Immun., July 1, 2000; 68(7): 4282 - 4288. [Abstract] [Full Text] [PDF] |
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J. George, Y. Shoenfeld, B. Gilburd, A. Afek, A. Shaish, and D. Harats Requisite Role for Interleukin-4 in the Acceleration of Fatty Streaks Induced by Heat Shock Protein 65 or Mycobacterium tuberculosis Circ. Res., June 23, 2000; 86(12): 1203 - 1210. [Abstract] [Full Text] [PDF] |
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M. Mosorin, H.-M. Surcel, A. Laurila, M. Lehtinen, R. Karttunen, J. Juvonen, J. Paavonen, R. P. Morrison, P. Saikku, and T. Juvonen Detection of Chlamydia pneumoniae-Reactive T Lymphocytes in Human Atherosclerotic Plaques of Carotid Artery Arterioscler. Thromb. Vasc. Biol., April 1, 2000; 20(4): 1061 - 1067. [Abstract] [Full Text] [PDF] |
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M. Menschikowski, A. Rosner-Schiering, R. Eckey, E. Mueller, R. Koch, and W. Jaross Expression of Secretory Group IIA Phospholipase A2 in Relation to the Presence of Microbial Agents, Macrophage Infiltrates, and Transcripts of Proinflammatory Cytokines in Human Aortic Tissues Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 751 - 762. [Abstract] [Full Text] [PDF] |
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A. Kol, A. H. Lichtman, R. W. Finberg, P. Libby, and E. A. Kurt-Jones Cutting Edge: Heat Shock Protein (HSP) 60 Activates the Innate Immune Response: CD14 Is an Essential Receptor for HSP60 Activation of Mononuclear Cells J. Immunol., January 1, 2000; 164(1): 13 - 17. [Abstract] [Full Text] [PDF] |
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