The inflammatory response in infectious and
autoimmune diseases is regulated by the balance between pro- and anti-inflammatory
cytokines. The
IL-1 complex contains polymorphic genes coding for IL-1alpha, IL-1beta and
IL-1Ra. The
IL-1Ra (variable number of tanden repeat) VNTR polymorphism has been shown to influence the capacity to produce IL-1beta and
IL-1Ra after in vitro stimulation. Allele 2 of this polymorphism is associated with a number of inflammatory diseases. To determine the impact of the
IL-1Ra polymorphism on in vivo human
cytokine synthesis, we used a
yellow fever vaccination model for the induction of
cytokine synthesis in healthy volunteers. Two different
yellow fever vaccines were used. After administration of the RKI
vaccine (34 volunteers), plasma
TNF-alpha concentration increased from 13.4 +/- 0.9 pg/ml to 23.3 +/- 1.1 pg/ml (P < 0.001), and plasma
IL-1Ra concentration increased from 308 +/- 25 pg/ml to 1019 +/- 111 pg/ml (P < 0.001), on day 2. Using Stamaril
vaccine, no increase in the plasma concentrations of either
TNF-alpha or
IL-1Ra could be detected (n = 17). Only the RKI
vaccine induced
TNF-alpha synthesis after in vitro stimulation of MNC. Carriers of allele 2 of the
IL-1Ra polymorphism had increased baseline concentrations of
IL-1Ra (350 +/- 32 pg/ml) compared with non-carriers (222 +/- 18 pg/ml, P < 0.001), and decreased concentrations of IL-1beta (0.9 +/- 0.2 pg/ml for carriers versus 2.8 +/- 0.7 pg/ml for non-carriers, P = 0.017). After
yellow fever vaccination (RKI
vaccine), no significant differences in the increase of
IL-1Ra plasma levels were detected between carriers and non-carriers of allele 2 of the
IL-1Ra gene polymorphism. This is the first study to examine the influence of this genetic polymorphism on in vivo-induced human IL-1beta and
IL-1Ra synthesis. Baseline concentrations of
IL-1Ra and IL-1beta were significantly influenced by the
IL-1Ra polymorphism. No influence of the
IL-1Ra polymorphism on the in vivo-induced production of
IL-1Ra and IL-1beta could be detected.