Tumor necrosis factor-α, lymphotoxin-α, and interleukin-10 gene polymorphisms and restenosis after coronary artery 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.
References (61)
- et al.
Regulation of cytokine signaling and inflammation
Cytokine Growth Factor Rev
(2002) - et al.
Multifunctional cytokine expression by human coronary endothelium and regulation by monokines and glucocorticoids
Microvasc Res
(1998) - et al.
H2O2 and tumor necrosis factor-α activate intercellular adhesion molecule 1 (ICAM-1) gene transcription through distinct cis-regulatory elements within the ICAM-1 promoter
J Biol Chem
(1995) - et al.
Interleukin-10 inhibits postinjury tumor necrosis factor-mediated human vascular smooth muscle proliferation
J Surg Res
(1998) Tumor necrosis factor locus: genetic organisation and biological implications
Hum Immunol
(1998)- et al.
TGF-β1, IL-10 and IL-4 differentially modulate the cytokine-induced expression of IL-6 and IL-8 in human endothelial cells
Cytokine
(1996) IL-10 inhibits the adhesion of leukocytic cells to IL-1-activated human endothelial cells
Immunol Lett
(1995)- et al.
Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation
J Am Coll Cardiol
(2000) - et al.
Protective role against restenosis from an interleukin-1 receptor antagonist gene polymorphism in patients treated with coronary stenting
J Am Coll Cardiol
(2000) - et al.
Haptoglobin phenotype and the risk of restenosis after coronary artery stent implantation
Am J Cardiol
(2002)
Haplotype associated with low interleukin-10 production in patients with severe asthma
Lancet
Genotyping for polymorphisms in interferon-γ, interleukin-10, transforming growth factor-β1 and tumour necrosis factor-α genes: a technical report
Transpl Immunol
Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome
Blood
Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction
Atherosclerosis
The tumor necrosis factor ligand and receptor families
N Engl J Med
Interleukin-10
Annu Rev Immunol
Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study
Circulation
Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses
Circulation
Pathology of acute and chronic coronary stenting in humans
Circulation
Morphologic predictors of restenosis after coronary stenting in humans
Circulation
Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1β in mediating the production of IL-8 triggered by lipopolysaccharide
J Exp Med
Tumor necrosis factor-α activates smooth muscle cell migration in culture and is expressed in the balloon-injured rat aorta
Arterioscler Thromb Vasc Biol
Re-evaluation of the chemotactic activity of tumour necrosis factor for monocytes
Immunology
Lymphotoxin α3 induces chemokines and adhesion molecules: insight into the role of LTα in inflammation and lymphoid organ development
J Immunol
Differential induction of adhesion molecule and chemokine expression by LTα3 and LTαβ in inflammation elucidates potential mechanisms of mesenteric and peripheral lymph node development
J Immunol
IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways
EMBO J
Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes
J Exp Med
Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein–Barr virus open reading frame BCRFI
Proc Natl Acad Sci U S A
IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells
J Immunol
Regulation of neutrophil-derived chemokine expression by IL-10
J Immunol
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