P.047 CCR5-DEL32 Genotype Modifies Pro-Inflammatory/ /Anti-Inflammatory Cytokine Ratio; Possible Role in Atherogenesis

Abstract

CCR5 is a receptor for several chemokines and is highly expressed on the cells involved in atherogenesis. A 32 bp deletion mutation of CCR5 prevents expression of this molecule on cell surface and is associated with reduced risk of premature coronary artery disease. It was shown that IL-6/IL-10 ratio could be a predictor of further coronary artery events in patients with Non-ST elevation acute coronary syndrome. In the present study we investigated the effect of CCR5-del32 mutation on production of pro-inflammatory and anti-inflammatory cytokines by lymphocytes in basal or stimulated conditions. Subjects were from a cohort of patients admitted to undergo coronary artery bypass graft surgery. Samples from 7 patients who were homozygote for wild type CCR5 allele (CCR5/CCR5) and 7 patients who were heterozygote for CCR5-del32 allele (CCR5/CCR5-del32) were used. Peripheral mononuclear cells (PMNC) were separated from whole blood by density gradient centrifugation. The PMNC cultures were either left untreated or incubated with lipopolysaccharide (LPS) or oxidative low density lipoprotein (OxLDL) for 24 hours before collecting their supernatant for cytokines measurement. PMNC carrying del32 produced significantly more IL-6 at baseline and after LPS stimulation. They also produced more IL-10 when stimulated with LPS and OxLDL. However, pro-inflammatory/anti-inflammatory ratio (IL-6/IL-10 and TNF-α/IL-10) tend to be lower under stimulation by LPS and OxLDL in the group with del32 genotype. We concluded that some aspects of the protective effect of CCR5-del32 mutation against premature atherosclerosis can be attributed to modulation of anti-inflammatory and pro-inflammatory cytokine response in inflammatory cells particularly in PMNC.