Elsevier

Cytokine

Volume 24, Issue 4, 21 November 2003, Pages 161-171
Cytokine

Tumor necrosis factor-α, lymphotoxin-α, and interleukin-10 gene polymorphisms and restenosis after coronary artery stenting

https://doi.org/10.1016/j.cyto.2003.08.004Get rights and content

Abstract

Inflammation is the primary response to vessel wall injury caused by stent placement in coronary arteries. The cytokines tumor necrosis factor (TNF)-α, lymphotoxin (LT)-α, and interleukin (IL)-10 are critically involved in inflammatory reactions. The intensity of the inflammatory process and the angiographic or clinical outcome after stenting are influenced by genetic factors. We investigated the possibility that single nucleotide polymorphisms of the genes encoding TNF-α (−863C/A, −308G/A), LT-α (252G/A), and IL-10 (−1082G/A, −819C/T, and −592C/A) are associated with the incidence of restenosis, death, or myocardial infarction (MI) after coronary stenting. The gene variations are known to be correlated with transcriptional activity and/or protein production. Our study included 1850 consecutive patients with symptomatic coronary artery disease who underwent stent implantation. Follow-up angiography was performed in 1556 patients (84.1%) at six months after the intervention. We found that the polymorphisms are not associated with restenosis, death, or MI. In addition, we did not observe a relationship between polymorphism-specific haplotypes and adverse angiographic and clinical outcomes. In conclusion, functionally relevant polymorphisms of the genes for TNF-α, LT-α, and IL-10 do not represent genetic markers indicating the risk of restenosis, death, or MI after coronary stenting.

Introduction

Tumor necrosis factor (TNF)-α, lymphotoxin (LT)-α, previously referred to as TNF-β, and interleukin (IL)-10 are considered key regulators of inflammatory responses and these cytokines may exert critical influences on the extent of neointima formation which is the dominant mechanism of restenosis in patients undergoing stent implantation in coronary arteries [1], [2], [3], [4]. Stent deployment inevitably causes mechanical injury of the arterial wall and, subsequently, elicits local inflammation, characterized by adhesion and invasion of inflammatory cells [5], [6]. Stent struts act as a local inflammatory stimulus and the degree of cell infiltration around stent struts is correlated with the severity of subsequent neointima formation [5], [6].

TNF-α has a broad spectrum of biologic activities and is predominantly known for its powerful proinflammatory effects [1], [7]. In response to different stimuli, TNF-α is produced by human macrophages, polymorphonuclear leukocytes, and vascular smooth muscle cells (VSMC) [1], [8], [9]. Treatment of human endothelial cells with TNF-α stimulates the synthesis of other proinflammatory cytokines and activates intercellular adhesion molecule-1 gene transcription [10], [11]. In addition, TNF-α has chemotactic activity for human monocytes and stimulates migration and growth of VSMC [9], [12], [13]. LT-α is structurally similar to TNF-α and the genes of the two factors are located next to each other within the human leukocyte antigen class III gene cluster on human chromosome 6p21 [14]. Several important functions of LT-α have been identified which suggest a significant role for this cytokine in inflammatory and chemoattractant responses, including induction of monocyte migration and promotion of lymphocyte activation and proliferation [12], [15], [16]. Due to their important roles in inflammatory processes, TNF-α and LT-α potentially contribute to neointima development at the site of stent placement.

IL-10 predominantly exerts antiinflammatory activities and its effects are mainly directed against functions of mononuclear cells, T lymphocytes, and polymorphonuclear leukocytes [2], [17]. Produced by different cell types, including human monocytes and T cells, IL-10 inhibits the production of proinflammatory cytokines, including TNF-α, probably by the induction of mechanisms directed against gene transcription and/or stability of mRNA [2], [7], [8], [18], [19], [20], [21], [22], [23], [24]. In human peripheral blood polymorphonuclear leukocytes, IL-10 interferes with the production of various chemokines, including IL-8, necessary to sustain the recruitment of different types of leukocytes for initiation or continued maintenance of an inflammatory process [21]. Treatment of IL-1-activated human endothelial cells with IL-10 results in lower surface densities of intercellular adhesion molecule-1 and vascular-cell adhesion molecule-1 and reduced leukocyte adhesivity [25]. In addition, IL-10 enhances the production of IL-1 receptor antagonist which has antiinflammatory activity directed against the effects of IL-1 [26]. In a randomized, controlled trial in healthy human volunteers, IL-10 showed inhibitory effects on T cells and suppressed production of the proinflammatory cytokines TNF-α and IL-1β [27]. Moreover, IL-10 interferes with intimal hyperplasia after balloon injury or stent implantation in hypercholesterolemic rabbits [28]. Together, existing evidence suggests that IL-10 restricts duration and extent of inflammatory reactions and attenuates intimal hyperplasia and restenosis.

Tight control of gene activity and protein production may equilibrate the pro- and antiinflammatory potentials of TNF-α, LT-α, and IL-10, respectively, and, in turn, prevent excessive inflammation and limit neointima formation [7]. However, imbalances in the regulation of this system may interfere with antiinflammatory effects and stimulate proinflammatory activities that result in neointima formation and restenosis. The genes encoding TNF-α, LT-α, and IL-10 contain variable sites that may be associated with different responsiveness to regulatory signals. In particular, single nucleotide polymorphisms (SNPs) located in the promoter regions of the TNF-α gene (−863C/A, −308G/A) and the IL-10 gene (−1082G/A, −819C/T, −592C/A), and in intron 1 of the LT-α gene (252G/A) were found to differentially affect binding of nuclear transcription factors, transcriptional activity and/or protein production [29], [30], [31], [32], [33], [34]. It was also reported that haplotypes defined by specific combinations of the alleles of the IL-10 SNPs are associated with IL-10 gene transcriptional activity and IL-10 production [35], [36]. These functionally relevant polymorphisms of the genes encoding TNF-α, LT-α, and IL-10 may be related to unfavourable outcomes after coronary interventions. We examined this possibility in a clinical association study which included a large series of patients with symptomatic coronary artery disease who were treated with stenting.

Section snippets

Results

In a population of 1850 patients who underwent stenting in coronary arteries, we determined the genotypes of the promoter polymorphisms −863C/A and −308G/A of the TNF-α gene, the intron 1 polymorphism 252G/A of the LT-α gene, and the promoter polymorphisms −1082G/A, −819C/T, and −592C/A of the IL-10 gene. The distributions of the genotypes were: 71.8% −863CC, 26.3% −863CA, 1.9% −863AA; 71.2% −308GG, 26.0% −308GA, 2.8% −308AA; 9.5% 252GG, 44.0% 252GA, 46.5% 252AA; 21.4% −1082GG, 47.9% −1082GA,

Discussion

Our assumption that a relationship exists between SNPs in the genes encoding TNF-α, LT-α, and IL-10 and the angiographic and clinical outcomes after stenting in coronary arteries was based on observations suggesting a critical role of inflammation in neointima formation, important regulatory functions of the cytokines in inflammatory processes, and the functional relevance of the SNPs [1], [6], [7], [29], [30], [31], [32], [33], [34]. Evidence indicating the importance of inflammation for

Limitations of the study

The patients examined in this study were Caucasians, and different results may be obtained with populations of other ethnic origins. Notably, allele and haplotype frequencies of the IL-10 SNPs in our and other white populations [50], [52], [53], [54] greatly differ from those reported of a Chinese population[56]. Another limitation of the study is the missing determination of cytokine plasma levels.

Patients

The study included 1850 consecutive white patients with symptomatic coronary artery disease who underwent coronary stent implantation in coronary arteries at Deutsches Herzzentrum München and 1. Medizinische Klinik rechts der Isar der Technischen Universität München. The protocols of stent placement and poststenting therapy were described in detail elsewhere [57], [58]. Postprocedural therapy consisted of aspirin (100 mg twice daily, indefinitely) and ticlopidine (250 mg twice daily for four

Acknowledgements

The authors thank Wolfgang Latz, Marianne Eichinger, Gisela Werner, and Angela Ehrenhaft for skilful technical assistance.

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