PRESENCE OF THE IL-1RA ALLELE-2 (IL1RN-ASTERISK-2) IS ASSOCIATED WITHENHANCED IL-1-BETA PRODUCTION IN-VITRO

The genes of the interleukin-1 (IL-1) complex code for three proteins: IL-1 alpha, IL-1 beta and the IL-1 receptor antagonist (IL-1RA). Each of these genes is polymorphic and there is increasing evidence that c ertain alleles are associated with increased susceptibility to a given disease of inflammatory nature. In the IL-1 beta gene there are two b ase-exchange polymorphisms in positions -511 and +3953, and IL-1RA gen e has a penta-allelic polymorphic site in intron 2 containing variable numbers of an 86-bp tandem repeat sequence. As the IL-1 beta/IL-1RA r atio may be critical in the regulation of inflammation, we examined wh ether there are allelic associations between these loci (thus suggesti ng co-ordinate regulation) and whether these have an effect on the in vitro production of IL-1 beta. We found that the LL-1RA allele 2 (IL1R N2) is associated with the presence of allele 2 of the IL-1 beta gene (position -511) and with the absence of allele 2 of the IL-1 beta gen e (position +3953). Mononuclear cells from carriers of allele 2 (posit ion -511) and non-carriers of allele 2 (position +3953) had a slight, but non-significant, elevated capacity to produce IL-1 beta in vitro. However, IL-1RA allele 2 strongly increased in vitro production of IL- 1 beta, regardless of the presence or absence of these alleles. Taken together, these data suggest that the known allelisms in the IL-1 beta gene are not major regulators of the in vitro IL-1 beta production, b ut the IL-1RA allele 2 (or an unknown allele strongly associated with it) has a decisive role.