Presence of the IL‐1RA Allele 2 (IL1RN*2) is Associated with Enhanced IL‐1β Production In Vitro

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Abstract
The genes of the interleukin‐1 (IL‐1) complex code for three proteins: IL‐1α, IL‐1β and the IL‐1 receptor antagonist (IL‐1RA). Each of these genes is polymorphic and there is increasing evidence that certain alleles are associated with increased susceptibility to a given disease of inflammatory nature. In the IL‐1β gene there are two base‐exchange polymorphisms in positions −511 and +3953, and IL‐1RA gene has a penta‐allelic polymorphic site in intron 2 containing variable numbers of an 86‐bp tandem repeat sequence. As the IL‐1β/IL‐1RA ratio may be critical in the regulation of inflammation, we examined whether there are allelic associations between these loci (thus suggesting co‐ordinate regulation) and whether these have an effect on the in vitro production of IL‐1β. We found that the IL‐1RA allele 2 (IL1RN*2) is associated with the presence of allele 2 of the IL‐1β gene (position −511) and with the absence of allele 2 of the IL‐1β gene (position +3953). Mononuclear cells from carriers of allele 2 (position −511) and non‐carriers of allele 2 (position +3953) had a slight, but non‐significant, elevated capacity to produce IL‐1βin vitro. However, IL‐1RA allele 2 strongly increased in vitro production of IL‐1β, regardless of the presence or absence of these alleles. Taken together, these data suggest that the known allelisms in the IL‐1β gene are not major regulators of the in vitro IL‐1β production, but the IL‐1RA allele 2 (or an unknown allele strongly associated with it) has a decisive role.