Environmental factors and not genotype influence the plasma level of interleukin-1 receptor antagonist in normal individuals

Abstract

Cytokine production may be regulated by both genotypic (single nucleotide or tandem repeat polymorphisms) and non-genotypic factors relating to the environment and inherent biology (i.e. gender). Interleukin (IL)-1 is one of the body's most highly proinflammatory cytokines and is implicated in the pathophysiology of numerous diseases, but also in the maintenance of homeostasis in a number of tissues. The cytokine IL-1 receptor antagonist (IL-1Ra) is the competitive inhibitor of the IL-1 agonists IL-1alpha and IL-1beta. In vivo IL-1Ra was measured in a cohort of 200 + blood donors and the effect of the IL-1 gene polymorphisms, environmental and biological factors assessed. In this study, we observed that possession of particular alleles of 5 IL-1 gene polymorphisms (IL1A-889, IL1Alpha VNTR, IL1B -511, IL1B +3953 and the IL1RN VNTR) did not correlate with higher plasma IL-1Ra levels. Environmental factors such as smoking and non-steroidal anti-inflammatory drug ingestion were associated with higher in vivo IL-1Ra levels (P = 0.015 and 0.022, respectively), but biological factors such as gender, age and menstruation status did not have any impact upon in vivo IL-1Ra levels. Genotypic associations of IL-1 gene family polymorphisms with disease features may reflect characteristics of stressed rather than normal control circuits for cytokine production.

Fig. 1

Allele frequencies of the five IL-1 gene polymorphisms studied in the NBA normal population, a comparative study by Hurme et al. [7] and those in previously reported studies; IL1A -889 [13]. IL1A VNTR [54], IL1B -511 [55], IL1B +3954 [56] and the IL1RN VNTR polymorphism. Gene locations are archived in the National Center for Biotechnology Information (NCBI) database [26].

Fig. 2

The effect of non-genotypic factors on plasma IL-1Ra levels. (a) Plasma IL-1Ra levels, comparing subjects for gender. There was no difference in plasma IL-1Ra levels between male and female blood donor volunteers. (b) Plasma IL-1Ra levels, comparing subjects for age. There was no difference in plasma IL-1Ra levels between blood donors > or <40 years of age. (c) Plasma IL-1Ra levels, comparing smokers and non-smokers. Smokers had higher plasma levels than non-smokers (P = 0·015). (d) Plasma IL-1Ra levels, examining the effect of NSAIDs. Those donors who had taken NSAIDs in the 2 weeks prior to donation also had higher plasma IL-1Ra levels (P = 0·022).