homozygotes and C allele carriers showed higher base- line and stimulated IL-6 levels. By contrast, Italian centenarians showed higher IL-6 levels in GG homo- zygotes who were male (Bonafe et al., 2001). Other ‘in vitro’ studies from this group, however, suggested an increase in IL-6 across the age groups in C allele subjects only (Olivieri et al., 2002). The reason for the dichotomy in these findings is not known but possible reasons might include differences in time between collection and cytokine measurement (Riches et al., 1992), different time release curves for cytokines (Burzotta et al., 2001) or ambient temperature. Other studies may have had insufficient statistical power, may have used different ELISA methods or different methods of collection, storage or assay of blood which could theoretically have allowed IL-6 to become released from activated cells (Riese et al., 2000; Muylle et al., 1993). The present study used Medegenix which is said to be unaffected by soluble inhibitors or enhancers and only measures biologically active IL-6. A further suggestion comes from a study which found that the activity of IL-6 -174 alleles may be reversed in different cell types, such as endothelial cells or macrophages. Such cells can secrete both IL-6 and IL-6 receptors and at variable times after inflammatory stimulus (Terry et al., 2000). Additionally, it has been suggested that linkage disequilibrium be- tween C/G 174 IL-6 and the 3?VNTR at IL-6 could explain the fact that in Alzheimer’s patients the CC genotype is associated with high levels of IL-6 (Fran- ceschi et al., 2001). However, it might be that study of other polymorphisms in tight linkage disequilibrium with the -174C/G IL-6 locus could throw light on the apparently contradictory findings.

This study in the BELFAST study of apparently well community-living octo/nonagenarians raises interesting questions about the role of the IL-6 C/G polymorphism in immune selection and longevity as well as informing about its role in the immunological balance of pro- inflammatory and anti-inflammatory cytokines. The reduction of frequency of GG homozygotes of the IL- 6 polymorphism of IL-6 which replicates the findings of the earlier Italian study (Bonafe et al., 2001) suggests that either IL-6 or some other polymorphism in closely linked disequilibrium may select for longevity especially in males. Clearly these interesting observations need confirmation in further studies where the issue and effect of the IL6 genotype on IL-6 levels would also need to be addressed.

In this study we also described the effect of the IL-6- 174 C/G polymorphism on serum soluble IL-6 receptor and IL-10, both of which can modulate IL-6 function in vivo (Hempel et al., 1995). Although soluble IL-6 receptor can enhance IL-6 function there was no evidence that the C/G polymorphism affected IL-6 soluble receptor levels in the BELFAST subject group. Interestingly, in this study we noted the novel finding that the C/G polymorphism of IL-6 had significant and reciprocal effects on serum IL-10 compared with its effect on IL-6, with higher levels of IL-10 being associated with carriage of the G allele. This suggests that up regulation of C/G polymorphism of the IL-6 gene initiates an intricate balancing act between pro- inflammatory effects of IL-6 and the modulatory activity of the powerful anti-inflammatory cytokine IL-10. Imbalances in the upregulation of IL-6-174 C/G gene could theoretically affect the IL-6 and IL-10 balance in vivo to influence acute and chronic diseases. Interestingly, recent evidence also shows that IL-6- 174C/G promoter activity affects baseline levels of plasma reactive protein (Vickers et al., 2002).

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