It has been reported that the immunopathological and inflammatory process plays an important role in the initiation and development of ischemic heart disease (IHD) [1]. http://dx.doi.org/10.1016/j.cyto.2016.04.006 1043-4666/
2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Department of Immunology, Medical School, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Tel.: +98 34 3433 9042; fax: +98 34 3433 9660. E-mail address: Jafarzadeh14@yahoo.com (A. Jafarzadeh). Cytokine 83 (2016) 147–157 Contents lists available at ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Besides the genetic parameters, hyperlipidemia, diabetes, hypertension, obesity and smoking are the major traditional cardiovascular risk factors, which induce endothelial injury. In the earliest stages of atherosclerotic lesion formation, activation of the endothelium in response to cardiovascular risk factors cause to the expression of chemokines and adhesion molecules. This, in turn, leads to monocyte and T cells recruitment into the subendothelial space [2]. The leukocytes recruited to the activated endothelium produce chemokines and cytokines, thus increasing the ongoing chronic inflammatory process at sites. This results in the presence of a large number of inflammatory cells within atherosclerotic lesions [2]. The aggregation of leukocytes such as monocytes/macrophages, T cells, B cells and PMN cells has been demonstrated within the atherosclerotic lesions [3]. The helper T (Th) cells-associated responses in particular, exert an important role in the pathogenesis of cardiovascular diseases [3,4]. The antigenic determinants of oxidized low density lipoprotein (OxLDL) and heat shock protein 60/65 (HSP60/65) may lead to the T cells activation within atherosclerotic lesions [3]. Upon antigenic stimulation, Th cells differentiate into Th1, Th2, Th17 and regulatory T (Treg) cells, which characterize by the release of distinct cytokines profile [3]. Th1 cells secrete cytokines including IFN-c and TNF-a, Th2 cells mainly secrete IL-4 and IL-5 and IL-13, Th17 cells principally secrete IL-17A and IL-17F and Treg cells produce TGF-b, IL-10 and IL-35 [4]. The cytokine environment which T cells encounter with it after antigenic stimulation determines the subsequent T cell polarization. IFN-c and IL-12 inducing Th1 cells differentiation, IL-4 stimulating Th2 cells development, both TGF-b and IL-6 were required for Th17 cells differentiation and Treg differentiation is dependent on the presence of TGF-b and IL-2 [5]. It should be also noted that Th1- and Th2 cellsrelated cytokines regulate each other response, so that IL-4 (a Th2 cytokine) inhibit Th1 cells differentiation whereas IFN-c (a Th1 cytokine) suppresses Th2 cells development [6]. The results of the some clinical and experimental studies have demonstrated that the up-regulation of Th1-associated inflammatory response and down-regulation of anti-inflammatory responses of Treg/Th2-related cytokines were associated with cardiovascular diseases [3,4]. Accordingly, the imbalance in the Th1/Th2 cellsrelated responses may be involved in the pathogenesis of IHD. However, the results of a number studies demonstrated that the Th1 cells are pro-atherogenic, Treg cells are athero-protective and the role of Th2 and Th17 cells remains unclear [3]. We have previously indicated higher levels a Th1-related cytokine (IL-18), increased concentrations of a Th17-related cytokine (IL-17A) and lower levels of a Th2-related cytokine (IL-13) in patients with IHD [7]. As mentioned, the recruitment of leukocytes is one of the earliest events in atherosclerosis and chemokines play an important role in the migration of these cells into inflammation sites [8]. Chemokines are a group of small polypeptide mediators (8–14 kDa), which attract various types of leukocytes to sites of infection and inflammation and regulate their Trafficking. Chemokines are classified into CXC, CC, CX3C or C chemokines based on the positioning of the conserved cysteine residues [2]. The involvement of the some chemokines (such as CCL2, CCL5, CCL19, CCL21, CXCL10, and CXCL16) and chemokine receptors (CCR1, CCR2, CCR5, CCR6, CCR7, CXCR2, CXCR3, CXCR4 and CXCR6) in lymphocyte homing into atherosclerotic lesions has been reported [2,9]. C-X-C motif ligand 10 (CXCL10), or interferon-inducible protein10, is secreted from neutrophils, eosinophils, monocytes, keratinocytes, epithelial and endothelial cells in response to IFN-c [10]. CXCL10 binds to its receptor, CXCR3, which is mainly being expressed on Th1 cells. Therefore, CXCL10 acts as a chemoattractant for leukocytes, especially Th1 lymphocytes [10,11]. Other effects of CXCL10 have been reported to be as activation and attraction of B lymphocytes, macrophages, and natural killer (NK) cells to the site of inflammation [11]. CXCL10 induces also migration and proliferation of endothelial cells and vascular smooth muscular cells [11]. The chemokine CXCL10 gene has been located on the chromosome 4q with several SNPs that may affect the chemokine production. The SNP -1447 A/G (rs4508917) in the CXCL10 gene, is among of the polymorphisms placed within the promoter region of the chemokine gene that may the influence the CXCL10 production [12,13]. The chemokine CCL20 is produced by some leukocytes in response to different cytokines [14]. The CCL20 receptor known as CCR6 and accordingly this chemokine acts as a chemoattractant for CCR6-expressing cells, such as Th17 cells [15]. Th17 cells express CCR6 and its ligand CCL20 [16], indicating that Th17 cells may regulate their own aggregation to inflamed tissues in an autocrine manner that may play an important role in supporting Th17 cells-mediated inflammation. The chemokine CCL20 gene has been mapped on the chromosome 2q33–37 [17] and we have selected a SNP -786 C/T (rs6749704) within its promoter region that may influence the chemokine production. Chemokine CCL22, also known as macrophage-derived chemokine (MDC) is produced by monocyte-derived macrophages and dendritic cells (DCs), upon the activation with microbial products or anti-CD40 antibody [18]. The CCL22 interacts with its receptor, CCR4, is preferentially expressed on Th2- and Treg cells [18]. The gene of CCL22 chemokine maps on the chromosome 16q13 with several SNPs, of which the SNP 16 C/A (rs4359426) may influence the chemokine activity [19]. The functional effect of SNP rs4359426 is replacing of GAT to GCT in coding region which result in a 2 Asp to 2 Ala replacement in the CCL22 protein [19]. As mentioned, the results of the some clinical and experimental studies have demonstrated that the up-regulation of Th1- and Th17 cells-associated inflammatory response and down-regulation of anti-inflammatory responses of Treg-/Th2 cells-related cytokines were associated with cardiovascular diseases, however the data on the chemokines that related to effector T cells are scarce and the relationship of chemokines with traditional risk factors of IHD, medication and gene polymorphisms is not fully clarified. Therefore, the aim of this study was also to evaluate the serum concentrations of CXCL10 (a Th1 type chemokine), CCL20 (a Th17 type chemokine) and CCL22 (a Th2-/Treg type chemokine) in patients with IHD (including AMI, SA and UA) and also to clarify their association with traditional risk factors of disease. It has been also indicated that the cytokine synthesis is controlled by genetic factors and certain SNPs in the cytokinerelated genes are associated with high or low cytokine production, which in turn may influence the susceptibility to certain diseases [20]. It has been also reported that the genetic variations in chemokine genes may influence the susceptibility to some infectious diseases and a variety of non-infectious diseases such as cancer, autoimmune and cardiovascular diseases [21]. The CXCL10, CCL20 and CCL22 gene polymorphisms have not been also investigated in patients with IHD, adequately. Therefore, the aim was also to evaluate the possible association of SNPs rs4508917 in CXCL10 gene, rs6749704 in CCL20 gene and rs4359426 in CCL22 gene in with IHD. We also assessed the association of the selected SNPs with serum levels of chemokines, thereby may provide insights regarding the functional relevance of these SNPs in IHD.