Interleukins (ILs) are key mediators in the chronic vascular inflammatory response underlying several aspects of cardiovascular disease. Due to their powerful pro-inflammatory potential, and the fact that they are highly expressed by almost all cell types actively implicated in atherosclerosis, members of the IL-1 cytokine family were the first to be investigated in the field of vessel wall inflammation. The IL-1 family is comprised of five proteins that share considerable sequence homology: IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-18 (also known as IFNgamma-inducing factor), and the newly discovered ligand of the ST2L receptor, IL-33. Expression of IL-1s and their receptors has been demonstrated in atheromatous tissue, and serum levels of IL-1-cytokines have been correlated with various aspects of cardiovascular disease and their outcome. In vitro studies have confirmed pro-atherogenic properties of IL-1alpha, IL-1beta and IL-18 such as, up-regulation of endothelial adhesion molecules, the activation of macrophages and smooth muscle cell proliferation. In contrast with this, IL-1Ra, a natural antagonist of IL-1, possesses anti-inflammatory properties, mainly through the endogenous inhibition of IL-1 signaling. IL-33 was identified as a functional ligand of the, till recently, orphan receptor, ST2L. IL-33/ST2L signaling has been reported as a mechanically activated, cardioprotective paracrine system triggered by myocardial overload. As the roles of individual members of the IL-1 family are being revealed, novel therapies aimed at the modulation of interleukin function in several aspects of cardiovascular disease, are being proposed. Several approaches have produced promising results. However, none of these approaches has yet been applied in clinical practice.

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Our results suggest that the genetic diversity of the interleukin-8 gene influences the clinical manifestation of CAD.

The potential regulatory effect of angiotensins on circulating mononuclear cell activation and migration has not yet been thoroughly evaluated. Using flow cytometry we assessed the possible effect of angiotensin I and II on the expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) in THP-1 monocytes, Jurcat T lymphocytes and primary monocytes-isolated from healthy donors. Fluorescence intensity and the rate of chemokine-positive cells was measured in naïve cells and cells treated with angiotensin I and II. Neither angiotensin I nor angiotensin II exhibited any effect on fluorescence intensity and the rate of CX3CR1-, CCR5- and CXCR4-positive cells in primary peripheral blood mononuclear cells and Jurkat T cells. However, angiotensin II significantly increased the rate of CX3CR1-positive THP-1 cells. This effect was not attenuated by the pre-incubation of THP-1 cells with the AT-1 receptor blocker losartan, suggesting that this was not an AT-1-mediated effect. Angiotensin I and II had no effect on fluorescence intensity and the rate of CCR5- and CXCR4-positive THP-1 cells. In conclusion, angiotensin II increases the rate of CX3CR1-positive THP-1 cells. By extrapolating this in vitro observation to disease mechanisms, we speculate that angiotensin II induces up-regulation of CX3CR1 and promotes firm adhesion of circulation CX3CR1-positive monocytes on CX3CL1 expressing endothelial cells inducing vascular inflammation and atherogenesis.

Genetic polymorphy of the distal promoter region of the ST2 gene influences transcriptional activity and susceptibility to atopic dermatitis and asthma. Based on the inflammatory background of atherosclerosis we hypothesized that ST2 distal promoter genetic polymorphy could also affect susceptibility to coronary artery disease (CAD). To test our hypothesis we performed direct sequencing of a 825 bp locus of the distal promoter -with previously reported significant polymorphy in 63 angiographically diagnosed CAD patients and 63 age and sex matched controls with negative coronary angiography. We identified 13 polymorphisms spanning this region two of which (-27307 T/A and -27614 C/A) had allele frequencies greater than 0.05. We further genotyped 111 subjects by applying allele-specific real-time PCR for the -27307 T/A and 27614 C/A polymorphisms, thereby increasing our sample to 129 CAD patients and 108 age- and sex-matched controls. We identified no phenotype-genotype interactions between cases and controls. However, among case subjects the severity of CAD expressed as a mean number of diseased vessels was greater in -27307 A allele carriers and either allele carriers (-27614 A or -27307 A) than in non-carriers (2.56 ± 0.73 vs. 1.83 ± 0.84, adjusted P = 0.027; 2.47 ± 0.74 vs. 1.8 ± 0.83, adjusted P = 0.023). Additionally, either allele carriers (-27614 A or -27307 A) were significantly more common in the multi-vessel disease group (n = 54) than in the single-vessel disease group (n = 75). In conclusion, we reported two new polymorphisms in the distal promoter region of the ST2 gene that possibly influence susceptibility to severe CAD. The functional impact of these polymorphisms remains to be determined.