Table 2 Functional IL-10/TNF-(cid:225) genotypes TNF-(cid:225) -308A carrier (A/A, A/G) TNF-(cid:225) -308G/G IL-10–1082A carrier (A/A, A/G) Low IL-10, high TNF-a Low IL-10, low TNF-a IL-10–1082G/G High IL-10, high TNF-a High IL-10, low TNF-a

IL-10–1082A carriers are classified as “low IL-10 producers”; IL-10–1082GG homozygotes are classified as “high IL-10 producers”; TNF-(cid:225) -308A carriers are classified as “high TNF producers”; TNF-(cid:225) -308GG homozygotes are classified as “low TNF producers”. For references, see text.

(QLK6-CT-1999-02031).Professor C Franceschi was funded by MIUR, Rome (ex 40%), Ministry of Health projects (1998 and 2001 “Chronic diseases prevention in ageing: the model of centenarians” and “Biological and genetic markers of successful and unsuccessful ageing”). LC is a PhD student in Pathobiology.

The isolated assessment of cytokine genotypes may be mis- leading without considering other interacting cytokines. In vivo control of TNF-a synthesis is complex and downregulated by anti-inflammatory cytokines including IL-10.12 13 The potential biological importance of this finding was high- lighted by a recent study showing a strong association between the combined low IL-10/high TNF-a genotype and early graft rejection in heart transplant recipients.14 Other recent studies have shown the complementary importance of IL-10 and TNF-a in patients with bacterial sepsis and have indicated an increased mortality in patients with a high plasma IL-10 to TNF-a ratio, that is, in patients with an anti- inflammatory phenotype (unfortunately in this study patients were not genotyped).43 Thus, in the light of different pathophysiological situations, it is difficult to assume a beneficial or detrimental effect of IL-10/TNF-a genotypes separately or in combination.So,inflammatory genotypes may be both friends and enemies. In fact, they are an important and necessary part of the normal host responses to pathogens, but the overproduction of inflammatory cytokines might cause immune-inflammatory diseases and eventually death. In particular, an anti-inflammatory genotype might be highly advantageous in the last decades of life owing to the chronic proinflammatory status, which develops in all the subjects with age. This phenomenon that we called inflamm-ageing is more evident in men than in women.14 This could be a possi- ble explanation for the higher frequency of the anti- inflammatory genotype we found in very old male subjects. We can also predict that the presence of the “high IL-10/low TNF-a ”genotype could be favourable in protecting against age related diseases such as AD and in elderly stroke.35 45 46



Authors’ affiliations

Correspondence to: Professor C Caruso, Gruppo di Studio dell’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, 90134 Palermo, Italy;

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