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Clinical Chemistry 51: 516-521, 2005. First published January 13, 2005; 10.1373/clinchem.2004.041277
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(Clinical Chemistry. 2005;51:516-521.)
© 2005 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Relationship between In Vitro Lipopolysaccharide-Induced Cytokine Response in Whole Blood, Angiographic In-Stent Restenosis, and Toll-Like Receptor 4 Gene Polymorphisms

Saskia Z.H. Rittersma1,a, Johanna A. Kremer Hovinga2, Karel T. Koch1, S. Matthijs Boekholdt1, Benien E. van Aken2, Arko Scheepmaker1, Matthijs Bax1, Carl E. Schotborgh1, Jan J. Piek1, Jan G.P. Tijssen1, Pieter H. Reitsma2 and Robbert J. de Winter1

Departments of1 Cardiology and 2 Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.

aAddress correspondence to this author at: Department of Cardiology, B2-115, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Fax 31-20-6962609; e-mail z.h.rittersma{at}amc.uva.nl.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
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Background: In coronary in-stent restenosis (ISR), a substantial contribution of inflammation is assumed. We evaluated the association between polymorphisms in the Toll-like receptor 4 (TLR4) gene and cytokine response after lipopolysaccharide (LPS) challenge and the development of ISR.

Methods: Patients were included after successful elective stent placement in a native coronary artery and were scheduled for follow-up angiography after 6 months. Quantitative coronary analysis was performed off-line. Patient whole blood was challenged with LPS for 24 h. Baseline and stimulated concentrations of interleukin (IL)-1ß, IL-6, tumor necrosis factor-{alpha}, and IL-10 were assessed by ELISA. Two cosegregating single-nucleotide polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) were analyzed by allele-specific PCR amplification of genomic DNA.

Results: A total of 236 consecutive patients were included, and 40 (17%) developed ISR. Median baseline and stimulated cytokine concentrations did not differ between patients with and without ISR. In multivariate analysis, male sex, unstable angina, hypertension, and chronic total occlusion were predictors of ISR. TLR4 genotypes were not associated with baseline or stimulated cytokine concentrations or with angiographic variables at follow-up.

Conclusions: In vitro cytokine response to LPS challenge is not increased in patients with ISR. Functionality of the TLR4 Asp299Gly polymorphism could not be demonstrated in this setting, and this polymorphism was not associated with angiographic outcome, calling into question its role in the progression of neointimal tissue growth.


   Introduction
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Materials and Methods
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In-stent restenosis (ISR) 1 is a complex process that involves local inflammatory responses. The concept of a substantial inflammatory role in the pathogenesis of restenosis has been supported by several investigations (1). Arterial wall injury induced by balloon inflation and stent placement is followed by a cascade of events, including sustained leukocyte infiltration in the arterial wall. The inflammatory cells are activated after injury and are capable of releasing mediators such as interleukin-1 (IL-1), tumor necrosis factor-{alpha} (TNF{alpha}), IL-6, and IL-10, which influence smooth muscle cell migration and proliferation (2)(3). The extent of the inflammatory response, including cytokine production, has been shown to vary individually and is based on genetic heterogeneity (4). Interindividual variations in this response may therefore reflect differences in the process of vascular tissue growth after stent implantation.

In the innate immune system, inflammatory cells can be activated by pathogens via the family of toll-like receptors. Toll-like receptor 4 (TLR4) can ligate with lipopolysaccharide (LPS), but can also be activated by cellular fibronectin in response to tissue injury (5) and by heat shock protein 60(6). This receptor is produced by monocytes and endothelial cells, and its production is markedly increased in human atherosclerotic lesions (7)(8) and was recently found to be involved in the development of intimal lesions in mice (9). Recently, two single-nucleotide polymorphisms in the gene encoding for TLR4 (Asp299Gly and Thr399Ile, giving rise to amino acid substitutions in the extracellular domain of the receptor) were found to have functional consequences by attenuating the TLR4 signaling pathway and leading to a blunted inflammatory response (10). In addition, these polymorphisms were associated with the risk of cardiovascular events in symptomatic men (11) and in patients with acute coronary syndromes (12).

Working from the assumption of a substantial inflammatory contribution to neointimal formation after stent placement, we hypothesized that interindividual variations in blood monocyte cytokine response to in vitro LPS challenge could reflect an individual’s susceptibility to develop angiographic ISR. We also evaluated the association of two polymorphisms of the TLR4 gene with cytokine response after LPS challenge and subsequent development of ISR.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study population and stenting procedure
A total of 236 consecutive patients were included in a single-center prospective observational cohort, the GEnetic risk factors for In-Stent Hyperplasia study Amsterdam (GEISHA), and the investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the local medical ethics committee, and all patients gave written informed consent after successful bare stent placement (MultiLink Guidant/Advanced cardiovascular systems, Inc.) in a native coronary artery. Indications for stent placement were bail-out or unsatisfactory result after balloon angioplasty alone, chronic total occlusions, ostial disease, and restenosis after balloon angioplasty. Exclusion criteria were ISR and complex lesions such as saphenous vein graft lesions, bifurcated lesions, lesions longer than 25 mm, reference vessel diameter <2.5 mm, and primary percutaneous transluminal coronary angioplasty (PTCA) for myocardial infarction. The procedure was considered successful when final diameter stenosis was <50%. Patients were treated with acetylsalicylic acid (100 mg) and Ticlopidine (250 mg) or Clopidogrel (75 mg) daily for 1 month after PTCA.

endpoint
The endpoint of this study was angiographic late luminal loss in minimal lumen diameter (MLD) and binary ISR (≥50% diameter stenosis), as documented on a scheduled angiography at 6–10 months of follow-up.

quantitative coronary analysis
Quantitative coronary analysis (QCA) was performed off-line on images obtained before and immediately after stent placement and at 6–10 months of follow-up, with a computerized QCA system (QCA-CMS, Ver. 5.0; MEDIS) (13). All angiograms were analyzed by a local core laboratory. The angiography was performed in at least two projections after intracoronary injection of isosorbide dinitrate (0.2 mg). The tip of a 6 or 7 French catheter, filled with contrast, was used for calibration. Acute luminal gain (mm) was defined as the difference between pre- and post-PTCA MLD, and late luminal loss (mm) was defined as the difference between MLD at follow-up and MLD immediately after PTCA. Binary ISR was defined as ≥50% diameter stenosis at the follow-up angiography. All continuous variables were calculated as mean values of two orthogonal views, using end-diastolic frames. The same views and calibration techniques were used at follow-up angiography.

in vitro challenge of whole blood by lps
To limit circadian variation in cytokine production, fasting blood samples were collected in the morning into pyrogen-free tubes (Sarstedt) containing pyrogen-free heparin (Thromboliquine® Organon; final concentration, 30 kIU/L). Blood samples were drawn 2 weeks after PTCA to avoid measuring the inflammatory response induced by stent placement. Heparinized blood aliquots (1 mL) were diluted 1:1 in Hank’s buffered saline solution (BioWhittaker) in pyrogen-free tubes (Falcon; Becton Dickinson) and incubated with LPS Escherichia coli 0111:B4 (Difco Laboratories) at a final concentration of 10 µg/L. After 24 h of incubation at 37 °C in a CO2 incubator, plasma was prepared by centrifugation at 800g for 10 min at 4 °C. Baseline cytokine concentrations were measured under similar conditions in the absence of LPS challenge. Cytokine concentrations were measured by commercial ELISAs for IL-1ß (detection limit, 2 ng/L), IL-6 (detection limit, 1.8 ng/L), IL-10 (detection limit, 2.4 ng/L), and TNF{alpha} (detection limit, 2.8 ng/L); all assays were commercially available PelikineTM assays manufactured by the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service "Sanquin", Amsterdam, The Netherlands (14). Calibrators provided in all assay reagent sets were used as for calibration. For all four ELISAs used, the CV was 5–8% over the whole measurement range. Measurements were performed in duplicate, and the mean value of two measurements was used. If the difference between the duplicates was >8%, the analysis was repeated. Samples below the detection limit were designated as having the lowest detectable value for the assays used. For leukocyte counts, blood was drawn into tripotassium EDTA tubes, and cell numbers were assessed routinely by flow cytometry (Technicon H1 system; Technicon Instruments).

genotyping
Genomic DNA was extracted from circulating leukocytes from all patients according to a standard protocol (15). TLR4 allele-specific PCR amplification was performed on 1 µL of DNA in 10 µL of ReddyMix (Abgene) according to previously described methods (16).

statistical analysis
Data are presented as the mean (SD), number (%), or as the median (range). Baseline cytokine concentrations are in ng/L, and stimulated cytokine concentrations are given as ng/106 monocytes. Continuous variables with gaussian distributions were compared by the Student unpaired t-test, and categorical variables were compared by the {chi}2 or Fisher exact test where appropriate. Continuous variables with an nongaussian distribution were compared by the Mann–Whitney test. Univariate linear regression analysis was performed to assess the predictive value of cytokine concentration for late luminal loss. Multivariate stepwise backward logistic regression analysis was performed to identify risk factors for ISR; univariate variables with a P value <0.2 were entered in the model. The statistical analysis was performed with the Statistical Package for Social Sciences software (SPSS 11.0 for Windows; SPSS Inc.). A P value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 236 patients were included, and angiographic follow-up was performed for all. The baseline clinical and angiographic characteristics of these patients are listed in Tables 1 and 2 . In total, 40 of the 236 patients (17%) had binary ISR.


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  		Table 1. Baseline clinical characteristics.


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  		Table 2. Angiographic characteristics at baseline and at follow-up.

The plasma cytokine concentrations are listed in Table 3 . Median baseline and post-LPS challenge concentrations of IL-1ß, IL-6, TNF{alpha}, and IL-10 did not differ between patients with and without binary angiographic ISR, and cytokine concentrations were not associated with late luminal loss. In addition, there were no age-, gender-, or statin therapy-related differences in baseline and stimulated cytokine concentrations. With multivariate backward stepwise logistic regression analysis, the model with male sex [odds ratio (OR) = 0.36; 95% confidence interval (CI), 0.17–0.79; P = 0.011], chronic total occlusion (OR = 2.5; 95% CI, 1.2–5.2; P = 0.015), hypertension (OR = 1.98; 95% CI, 0.9–4.2; P = 0.076), and unstable angina pectoris (OR = 0.3; 95% CI, 0.1–1.03; P = 0.057), but none of the cytokine concentrations, was best predictive for the occurrence of ISR.


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  		Table 3. Cytokine concentrations at baseline and after LPS-challenge, relative to ISR.

In the present cohort, 230 of 236 patients (97%) were successfully genotyped for the TLR4 polymorphisms; 31 carried the 299Gly allele (denoted as 299Gly-positive), and 28 carried the 399Ile allele (399Ile-positive). The three common genotype combinations (normal TLR4, denoted as 299AspAsp; 299Gly carriership in the presence of 399Ile carriership, denoted as 299Gly-positive/399Ile-positive; and 299Gly carriership in the absence of 399Ile carriership, denoted as 299Gly-positive/399Ile-negative) were found at frequencies of 0.87, 0.12, and 0.013, respectively. Because of the small number of patients with the 299Gly-positive/399Ile-negative genotype (n = 3), these patients were analyzed together with the 299Gly-positive/399Ile-positive genotype. For the total cohort, the observed allele frequencies were in Hardy–Weinberg equilibrium.

Carriership of the TLR4 299Gly allele was not associated with decreased baseline or LPS-challenged IL-1ß, IL-6, TNF{alpha}, and IL-10 concentrations when compared with noncarriers (Table 4 ). In addition, angiographic variables at follow-up were not associated with the Asp299Gly polymorphism (Table 5 and Fig. 1 ).


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  		Table 4. Cytokine concentrations at baseline and after LPS challenge according to TLR4 genotype.


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  		Table 5. Angiographic follow-up according to TLR4 genotype.



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  		Figure 1. Cumulative frequency distribution of late luminal loss in patients with the 299Gly-positive genotype (gray line) and patients with the 299AspAsp genotype (black line).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we investigated whether the risk of coronary ISR can be predicted by interindividual differences in inflammatory response to in vitro LPS challenge in whole blood. The results showed that angiographic variables at follow-up were not associated with baseline cytokine concentrations or with the production of IL-1ß, IL-6, TNF{alpha}, or IL-10 in response to in vitro LPS challenge at 24 h. Interestingly, the differences in response could not be explained by the TLR4 Asp299Gly polymorphism; in addition, this polymorphism was not associated with angiographic outcome.

The involvement of inflammation and the role of cytokines in the complex process of restenosis have been investigated extensively (1). Pietersma et al.(17) showed in a small group of patients that relative late luminal loss could be predicted by the production of IL-1ß by stimulated monocytes. However, baseline plasma concentrations of IL-1ß and stimulated IL-6 and TNF{alpha} concentrations were not associated with angiographic outcome. Hojo et al. (18) showed that high IL-6 concentrations in the coronary circulation after PTCA were associated with an increased risk of restenosis, although the sample size was small and stent placement was performed in only 12 patients. Recently, plasma IL-6 concentrations at follow-up, but not IL-10 concentrations, were found to be associated with restenosis in 42 patients treated with coronary stent placement, suggesting that a persisting low-grade inflammatory response promotes neointimal growth (19). Two experimental studies in rabbits showed an increase in neointimal formation induced by systemic inflammation (20) and a decrease in intimal hyperplasia after treatment with recombinant IL-10 (21). The study by Feldman et al. (21) suggested an antiproliferative effect of the antiinflammatory cytokine IL-10.

We previously showed that stent placement in humans is followed by abundant cellular infiltration around the metal stent struts (22), indicating a local inflammatory response. Our present results on systemic indicators of inflammation were all negative, although they were in accordance with our previous negative results for C-reactive protein as a prognostic marker for angiographic ISR (23). To our knowledge, our study is the first attempt to associate individual differences in cytokine production with angiographic outcome in a large cohort of patients, all treated electively with the same coronary stents. We hypothesized that patients who responded with high concentrations of proinflammatory cytokines after in vitro LPS challenge would have exaggerated vascular tissue growth during the 6–10 months after stent placement. However, both dichotomous and continuous angiographic variables showed a consistent lack of association with baseline and stimulated cytokine concentrations, although baseline differences may have been present below the assay detection limits. The injection of LPS in humans is a well-known model for studying host responses to acute systemic inflammation. The in vitro challenge of whole blood is suggested to reflect this in vivo response and enables differentiation between high and low cytokine responders (24). The negative outcome of our study regarding this response indicates that interindividual variability does not reflect the variability in the local inflammatory response to tissue injury by PTCA or the prolonged stent-induced tissue response. However, any differences in endogenous baseline cytokine concentrations may have been obscured by the differences in response to LPS.

Considering the reported frequency of the 299Gly-positive variant, our study population was within the expected range (allele frequency, 6.7%) (11)(25)(26), indicating that our cohort did not reflect a selected population. For the comparison of cytokine concentrations between different genotypes, we combined 299Gly-positive/399Ile-positive patients with 299Gly-positive/399Ile-negative patients because of the limited number of patients with the latter genotype (n = 3). As a result, we cannot be conclusive about the separate functionality of the Thr399Ile gene polymorphism.

The results of our present study showed that the common Asp299Gly polymorphism in the TLR4 gene does not affect cytokine response to LPS stimulation. In contrast to our hypothesis, patients with a 299Gly-positive genotype did not show diminished concentrations of cytokines. In addition, this genotype was not associated with better angiographic outcome.

The role of TLR4 and these gene polymorphisms in inflammatory and atherosclerotic disease has been investigated in both experimental and clinical studies. Recently, Boekholdt et al. (11) found a decreased risk of coronary events in men with documented coronary artery disease who were carriers of the 299Gly allele, compared with noncarriers, although this genotype was not associated with progression of atherosclerosis. This observation was confirmed by the Southampton Atherosclerosis Study, which showed a lack of association between the genotype and progression of coronary artery disease (26). These data are consistent with our angiographic outcome after 6 months, showing that the TLR4 genotype did not affect late luminal loss as a reflection of neointimal tissue growth. However, data concerning the functionality of this common TLR4 gene variant are limited and conflicting. In the Bruneck study by Kiechl et al. (25), baseline plasma IL-6 concentrations, among other markers of inflammation, were significantly decreased in carriers of the 299Gly allele. The experimental model in humans used by Arbour et al. (10) indicated that 299Gly-positive/399Ile-positive allele carriers had a significantly blunted response of IL-1{alpha} and TNF{alpha} after inhaling LPS. In contrast, our results are consistent with the report from Von Aulock et al. (27), who did not find a significant association between this genotype and cytokine response after a LPS challenge, similar to ours, in healthy volunteers. Whether the duration of LPS challenge or the LPS concentration used may have concealed early differences in response or differences based on threshold of activation could be a topic for discussion, but Von Aulock et al. (27) showed that both carriers and noncarriers responded equally to different dosages of LPS.


   Acknowledgments
 
J.A.K.H. was supported by a grant from the Swiss National Foundation for Scientific Research. We thank Angelique P.A. Groot from the Laboratory for Experimental Internal Medicine (AMC) for excellent technical assistance.


   Footnotes
 
1 Nonstandard abbreviations: ISR, in-stent restenosis; IL, interleukin; TNF{alpha}, tumor necrosis factor-{alpha}; TLR4, Toll-like receptor 4; LPS, lipopolysaccharide; PTCA, percutaneous transluminal coronary angioplasty; MLD, minimal lumen diameter; QCA, quantitative coronary analysis; OR, odds ratio; and 95% CI, 95% confidence interval.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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