(Circulation. 1999;100:1369-1373.)
© 1999 American Heart Association, Inc.
Brief Rapid Communication |
Chlamydia pneumoniae Infection of Vascular Smooth Muscle and Endothelial Cells Activates NF-
B and Induces Tissue Factor and PAI-1 Expression
A Potential Link to Accelerated Arteriosclerosis
From the Max Delbrück Center for Molecular Medicine (R. Dechend, C.S., A.L.), Berlin; Medical University of Lübeck (M.M., J.G.), Institute for Medical Microbiology and Hygiene, Lübeck; and Charité, Humboldt University at Berlin (R. Dietz, D.C.G.), Franz-Volhard Clinic, Berlin, Germany.
Correspondence to Ralf Dechend, MD, Max Delbrück Center for Molecular Medicine, Robert Rössle Str 10, D-13122 Berlin, Germany. E-mail rdechend{at}mdc-berlin.de
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Abstract |
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Background—Recent reports link C. pneumoniae infection of arteriosclerotic lesions to the precipitation of acute coronary syndromes, which also feature tissue factor and plasminogen activator inhibitor 1 (PAI-1) overexpression. We investigated whether or not C. pneumoniae can induce thrombogenicity by upregulation of procoagulant proteins.
Methods and Results—Human vascular endothelial
and smooth muscle cells were infected with a strain of C.
pneumoniae isolated from an
arteriosclerotic coronary artery. Tissue
factor, PAI-1, and interleukin-6 expression was increased in infected
cells. Concomitantly, NF-
B was activated and IB
degraded. p50/p65 heterodimers were identified as the components
responsible for the NF-B activity.
Conclusions—These data provide evidence that C.
pneumoniae infection can induce procoagulant protein and
proinflammatory cytokine expression. This cellular response is
accompanied by activation of NF-B. Our results demonstrate how
C. pneumoniae infection may initiate acute
coronary syndromes.
Key Words: plasminogen activator inhibitor 1 • tissue factor • interleukins • arteriosclerosis • C. pneumoniae
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Arteriosclerosis involves genetic and environmental influences.1 In addition to gradual arteriosclerotic progression, plaque erosion and rupture may occur with mural thrombosis, sudden luminal narrowing, or abrupt vessel closure. The clinical consequence is the acute coronary syndrome (ACS).2 Recent data from epidemiological, histopathological, and intervention studies suggest a role of C. pneumoniae infection in the pathogenesis of ACS.3 4 However, the molecular mechanisms are poorly understood. Macrophages may be recruited to the plaque causing weakening of the fibrous cap and subsequent plaque rupture.5 Thrombogenicity participates in the precipitation of ACS.6 We reasoned that C. pneumoniae infection might increase the thrombogenicity of infected plaques. We examined tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) expression in human vascular smooth muscle (VSMC) and endothelial cells (EC). Increased TF, PAI-1, and interleukin-6 (IL-6) were found after C. pneumoniae infection. Enhanced thrombogenicity was accompanied by sustained activation of the nuclear transcription factor NF-
B p50/p65
heterodimer and the simultaneous degradation of the
inhibitor protein IB. Our findings suggest that
C. pneumoniae infection induces procoagulant protein and
proinflammatory cytokine expression via NF-B activation. We
suggest that this process may precipitate ACS. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C. pneumoniae infection was established in primary cultures of human VSMCs (Clonetics, San Diego, Calif) and in the immortalized human venous endothelial cell line ECV-304 (ATCC CRL 1998). Stock suspensions were prepared from the vascular C. pneumoniae strain CV-4, isolated from an arteriosclerotic coronary artery as described earlier.7 C. pneumoniae growth was monitored 72 hours after infection using a fluorescein isothiocyanate-conjugated C. pneumoniae-specific monoclonal antibody (DAKO, Copenhagen, Denmark). Cells were also continuously checked for detachment from plates and cell lysis. Cells were harvested at different time points for electrophoretic mobility shift assay (EMSA) and lysed in whole cell lysate buffer. Labeling and binding reaction were performed as described.8 The DNA probe contained the
B site from the MHC-enhancer (H2K) or the H2B octamer
binding site. EMSAs were repeated 3 times and
representative gels are shown. Polyclonal antisera to
NF-B proteins p50, p65, c-Rel, and RelB were purchased from Santa
Cruz Biotechnology Inc, Calif. For immunoblotting,
whole cell lysates were prepared, quantified by standard Bradford
assay, and immunoblotting was performed as
described.9 TF and PAI-1 were obtained from Loxo (GmbH,
Dossenheim, Germany); IL-6 and tubulin from Genzyme (Framinghman,
Mass). Protein concentrations of the cellular supernatants were
quantified for ELISA using the Bradford method. IL-6 (Quantikine
Immunoassay, R&D Systems, Minneapolis Minn) and PAI-1 (American
Diagnostics, Greenwich, Conn) were determined by ELISA. TF
activity was determined in cell extracts with a clotting based assay
(ACTICLOT, Diagnostics International, Karlsdorf,
Germany). |
Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Figure 1A
shows infection of human
ECs and VSMCs. Intracellular inclusion bodies are visible, they contain
actively replicating C. pneumoniae of the CV-4 strain
isolated from infected coronary
plaques.10
|
and • represent supernatant PAI-1
and IL-6 levels in infected and mock-infected
endothelial cells, respectively, determined by ELISA
(center and right). Data and standard deviation represent mean
of triplicates.
Figure 1B
shows TF, PAI-1, tubulin, and IL-6 expression in
cellular EC lysates. TF expression was increased 4 hours after
infection, reached maximum by 48 hours, and was sustained for the
entire 72-hour study period. Increased PAI-1 expression plateaued at 4
hours and was sustained throughout the 72 hours (Figure 1B).
Tubulin expression was not influenced by infection, whereas IL-6
expression was increased by 4 hours. Similar effects were found in
VSMCs; however, C. pneumoniae-induced TF and PAI-1
expression was lower in VSMCs than in ECs, as demonstrated by
quantification (Figure 1B). In the supernatant of infected ECs,
PAI-1 and IL-6 levels were induced nearly 4- and 6-fold, respectively,
and remained elevated throughout the 72 hours of study (Figure 1C, center and right). In addition, as shown by a functional
assay, TF coagulant activity of the cellular extracts increased to a
similar extent as TF protein expression (Figure 1C, left).
NF-B is an important transcriptional regulator for TF and IL-6
expression.11 12 Moreover, additional data suggest that
PAI-1 expression is also under the control of
NF-B.13 14 Furthermore, NF-B is activated by
microbial infection.15 EMSA results are shown in Figure 2A. NF-B activity was increased at 4
hours after C. pneumoniae infection and persisted over 72
hours in ECs and VSMCs. However, the DNA-protein complex formation
shows somewhat different time-steps in the two cell types.
The induced DNA complexes observed at 4 hours postinfection in
HASMCs remain almost constant during the entire observation period. In
ECs, however, transient DNA-protein complex was detected 24 hours
postinfection in ECs. Only weak NF-B DNA binding activity was seen
in both mock-infected cell types. Competitive inhibition by unlabeled
H2K oligonucleotides, but not by an AP-1 DNA binding
site (Figure 2B), suggests specificity of the interaction.
Moreover, activation of NF-B was specific because the DNA binding
activity of endogenous octamer-binding transcription factor
1 was not affected (Figure 2A). We performed antibody supershift
experiments to determine which components of the NF-B family were
activated by C. pneumoniae. Addition of p65 and p50,
but not p52, c-Rel, or RelB antibodies, resulted in supershifts (Figure 2B).
Immunoblot analysis demonstrated that
C. pneumoniae infection was associated with a loss of
IB protein, starting at 4 hours and reaching a maximum at 48
hours (Figure 2C). IB levels were restored by 72 hours.
Taken together, these data show that C. pneumoniae infection
results in NF-B p50/p65 heterodimer activation and expression of
procoagulant and proinflammatory proteins.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The important findings in this study were that C. pneumoniae infection of human EC and VSMC resulted in TF, PAI-1, and IL-6 overexpression. Moreover, we demonstrated that C. pneumoniae infection resulted in NF-
B activation. NF-B
remained upregulated for at least 72 hours and was accompanied by
IB degradation. Although C. pneumoniae belong to the
eubacteria, they have no close relatives among the known bacterial
genera and a direct activation of NF-B by C. pneumoniae
infection has not been shown thus far. Plaque rupture and increased thrombogenicity are prime mechanisms of ACS.2 6 Because chronic C. pneumoniae infection is linked to the precipitation of ACS,3 4 we examined whether infections with a C. pneumoniae strain isolated from such a coronary plaque would increase the expression of prothrombotic proteins in vascular cells. We found induced and sustained expression of functionally active TF and PAI-1. Our results agree with reports from Rickettsia rickettsii-infected ECs overexpressing TF, PAI-1, IL-1, IL-6, and IL-8.16 Furthermore, infection of ECs with different Chlamydia strains also induce TF overexpression.17 Thus, the alteration of the epi/pericellular hemostatic protein expression observed here is not necessarily specific for the vascular C. pneumoniae strain that we used.
In addition to an increased procoagulation protein expression,
functional cytokines are expressed in human
arteriosclerotic lesions.1 IL-6 is an
important mediator of inflammation in cardiovascular
tissue.18 IL-6 is highly expressed in
arteriosclerotic lesions,19 implicated
in plaque instability,20 and in the pathogenesis of acute
myocardial infarction.18 C. pneumoniae
infection induced sustained cellular overexpression and secretion of
IL-6. Recruitment of mesenchymal and immunocompetent cells,
proliferation, and migration of VSMCs are the consequences of
cytokine overexpression in the
arteriosclerotic plaque.21 This
state of affairs further perturbs the anticoagulant activities. The
functional cooperation between products of the coagulation cascade
and cytokine-mediated inflammatory response has been shown to
transform a stable plaque into an unstable plaque.21 In
this context, colocalization of human heat shock protein 60 (hsp) with
chlamydial hsp 60 in macrophages was demonstrated. Both hsp
forms induced proinflammatory cytokines such as TNF- and
metalloproteinases.5
TF and IL-6 are transcriptionally regulated by
NF-B.11 12 Furthermore, data have been
presented that PAI-1 protein expression is also under the
control of NF-B.13 However, these data are less
compelling. In addition, inhibition of TNF-–induced PAI-1, TF, and
IL-6 activation was achieved when NF-B activity was inhibited with
the antioxidant pyrrolidine dithiocarbamate.14 Therefore,
current knowledge suggests a common link between C.
pneumoniae infection, TF, PAI-1, IL-6 expression, and NF-B. We
therefore investigated whether NF-B activity is induced in response
to C. pneumoniae infection. We showed that after
infection, p50/p65 heterodimer activity was upregulated in association
with degradation of IB. Our findings therefore suggest that the
C. pneumoniae-induced overexpression of TF, PAI-1, and IL-6
is transcriptionally regulated by NF-B.
Recent data underscored the role of NF-B in the pathogenesis of
arteriosclerosis.15 22 ECs, VSMCs, and
macrophages harvested and grown from
arteriosclerotic lesions express activated
NF-B. Our findings are consistent with data showing that
R. rickettsii-induced TF overexpression was controlled by
NF-B.16 R. rickettsii are not
phylogenetically related; however, they share characteristics with
C. pneumoniae, including obligate intracellular lifestyle,
Gram-negative cell wall composition, and the ability to infect ECs.
Interestingly, R. rickettsii has been shown to mediate
NF-B induced transcriptional activation, resulting in the inhibition
of EC apoptosis.23 A similar mechanism in
C. pneumoniae infection might provide an explanation for
chlamydial persistence in the endothelium and a
continuous inflammatory stimulus within the vascular wall. We are the
first to show that NF-B is activated in response to C.
pneumoniae infection.
Our data suggest that chronic C. pneumoniae infection in the
cellular components of plaques can result in increased cellular and
epi/pericellular procoagulant protein expression and increased
chemoattractant activity through activated NF-B. Both
effects could enhance the vulnerability of
arteriosclerotic plaques. Our results add to the
understanding of the role of C. pneumoniae bacteria in the
mechanism of accelerated arteriosclerotic
disease.
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Acknowledgments |
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R. Dechend and M.M. were supported by the Deutsche Forschungsgemeinschaft (DE-631/1-1) and (Ma 2070/2-1).
Received June 25, 1999; revision received August 10, 1999; accepted August 10, 1999.
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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]
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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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A. Tiran, H.-J. Gruber, W. F. Graier, A. H. Wagner, E. B.M. van Leeuwen, and B. Tiran Aspirin Inhibits Chlamydia pneumoniae-Induced Nuclear Factor-{kappa}B Activation, Cytokine Expression, and Bacterial Development in Human Endothelial Cells Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1075 - 1080. [Abstract] [Full Text] [PDF]
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T. Vainas, H. A.J.M. Kurvers, W. H. Mess, R. d. Graaf, R. Ezzahiri, J. H.M. Tordoir, G.-W. H. Schurink, C. A. Bruggeman, and P. J.E.H.M. Kitslaar Chlamydia pneumoniae Serology Is Associated With Thrombosis-Related but Not With Plaque-Related Microembolization During Carotid Endarterectomy Stroke, May 1, 2002; 33(5): 1249 - 1254. [Abstract] [Full Text] [PDF]
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N. Parchure, E. G. Zouridakis, and J. C. Kaski Effect of Azithromycin Treatment on Endothelial Function in Patients With Coronary Artery Disease and Evidence of Chlamydia pneumoniae Infection Circulation, March 19, 2002; 105(11): 1298 - 1303. [Abstract] [Full Text] [PDF]
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 E. L. Marston, A. V. James, J. T. Parker, J. C. Hart, T. M. Brown, T. O. Messmer, D. L. Jue, C. M. Black, G. M. Carlone, E. W. Ades, et al. Newly Characterized Species-Specific Immunogenic Chlamydophila pneumoniae Peptide Reactive with Murine Monoclonal and Human Serum Antibodies Clin. Vaccine Immunol., March 1, 2002; 9(2): 446 - 452. [Abstract] [Full Text] [PDF]
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 R. Tavendale, D. Parratt, S.D. Pringle, R. A'brook, and H. Tunstall-Pedoe Serological markers of Chlamydia pneumoniae infection in men and women and subsequent coronary events. The Scottish Heart Health Study Cohort Eur. Heart J., February 2, 2002; 23(4): 301 - 307. [Abstract] [Full Text] [PDF]
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K. Rajalingam, H. Al-Younes, A. Muller, T. F. Meyer, A. J. Szczepek, and T. Rudel Epithelial Cells Infected with Chlamydophila pneumoniae (Chlamydia pneumoniae) Are Resistant to Apoptosis Infect. Immun., December 1, 2001; 69(12): 7880 - 7888. [Abstract] [Full Text] [PDF]
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C. Wahl, F. Oswald, U. Simnacher, S. Weiss, R. Marre, and A. Essig Survival of Chlamydia pneumoniae-Infected Mono Mac 6 Cells Is Dependent on NF-kappa B Binding Activity Infect. Immun., November 1, 2001; 69(11): 7039 - 7045. [Abstract] [Full Text] [PDF]
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 J.C. Kaski and E.G. Zouridakis Inflammation, infection and acute coronary plaque events Eur. Heart J. Suppl., August 1, 2001; 3(suppl_I): I10 - I15. [Abstract] [PDF]
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G. Wang, Y. L. Siow, and K. O Homocysteine induces monocyte chemoattractant protein-1 expression by activating NF-{kappa}B in THP-1 macrophages Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2840 - H2847. [Abstract] [Full Text] [PDF]
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 J. Witowski, A. Thiel, R. Dechend, K. Dunkel, N. Fouquet, T. O. Bender, J. M. Langrehr, G. M. Gahl, U. Frei, and A. Jorres Synthesis of C-X-C and C-C Chemokines by Human Peritoneal Fibroblasts : Induction by Macrophage-Derived Cytokines Am. J. Pathol., April 1, 2001; 158(4): 1441 - 1450. [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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R. G. J. Gibbs, M. Sian, A. W. M. Mitchell, R. M. Greenhalgh, A. H. Davies, and N. Carey Chlamydia pneumoniae Does Not Influence Atherosclerotic Plaque Behavior in Patients With Established Carotid Artery Stenosis Stroke, December 1, 2000; 31(12): 2930 - 2935. [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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D. N. Muller, E. M. A. Mervaala, R. Dechend, A. Fiebeler, J.-K. Park, F. Schmidt, J. Theuer, V. Breu, N. Mackman, T. Luther, et al. Angiotensin II (AT1) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-Induced Cardiac Vasculopathy Am. J. Pathol., July 1, 2000; 157(1): 111 - 122. [Abstract] [Full Text] [PDF]
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J. Rodel, M. Woytas, A. Groh, K.-H. Schmidt, M. Hartmann, M. Lehmann, and E. Straube Production of Basic Fibroblast Growth Factor and Interleukin 6 by Human Smooth Muscle Cells following Infection with Chlamydia pneumoniae Infect. Immun., June 1, 2000; 68(6): 3635 - 3641. [Abstract] [Full Text] [PDF]
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R. Dechend, V. Homuth, G. Wallukat, J. Kreuzer, J. K. Park, J. Theuer, A. Juepner, D. C. Gulba, N. Mackman, H. Haller, et al. AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor Circulation, May 23, 2000; 101(20): 2382 - 2387. [Abstract] [Full Text] [PDF]
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 N. Hill-Kapturczak, L. Truong, V. Thamilselvan, G. A. Visner, H. S. Nick, and A. Agarwal Smad7-dependent Regulation of Heme Oxygenase-1 by Transforming Growth Factor-beta in Human Renal Epithelial Cells J. Biol. Chem., December 22, 2000; 275(52): 40904 - 40909. [Abstract] [Full Text] [PDF]
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