IL-10 is both an immunoinhibitory (monocytes and T cells) and an immunostimulatory (B cells) cytokine that may confer susceptibility and modulate disease expression in rheumatoid arthritis (RA). The capacity to produce IL-10 (as measured by production of IL-10 in a lipopolysaccharide-stimulated whole blood culture) differs about fourfold between individuals. By comparing variance between monozygotic and dizygotic twins it was estimated that 60% of these differences are caused by genetic factors.
To determine relevance for susceptibility to diseases, we determined production levels of IL-10 in lipopolysaccharide-induced whole blood cultures from 76 new incident, non-treated RA patients and 63 healthy controls. RA patients had a 50% lower IL-10 production than controls (P < 0.001). In a cohort of women (≥ 85 years) with high risk of cardiovascular death , we observed that low innate IL-10 production yielded a threefold increase in risk of dying, which, interestingly, correlates with the presence of the A allele of the IL-10 -2849 promoter polymorphism (P = 0.021).
To elucidate this genetic basis of IL-10 secretion and the functionality of IL-10 promoter polymorphisms, we used the technique of allele-specific transcript quantification to characterise the ratio between two alleles of the IL-10 gene in 15 healthy heterozygous individuals. We identified two groups whereby five healthy donors exhibited a 1:1 ratio whereas seven exhibited a ratio >1 (P < 0.0017) . Donors heterozygous for haplotype IL-10.2 were only prevalent in the group with higher allelic expression ratios. The G allele of the IL-10 promoter single nucleotide polymorphism -2849 tags this haplotype, providing functional evidence that differential allelic transcription partly explains the constant associations found with IL-10 production levels.
In conclusion, this study provides evidence that IL-10 haplotypes dictating production of IL-10 are involved not only in conferring susceptibility to RA, but also in risk for cardiovascular death in old age.
Van Den Biggelaar AH, De Craen AJ, Gussekloo J, Huizinga TW, Heijmans BT, Frolich M, Kirkwood TB, Westendorp RG: Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming.