Interleukin-18 (-1297T/C; -137G/C) polymorphisms showed significant association with genetic susceptibility to the disease in our systemic lupus erythematosus cohort.
The P2X7R-inflammasome axis in addition to the direct production of IL-1β and IL-18, indirectly mediates the release of other cytokines implicated in the pathogenesis of SLE, such as IL-6.
In conclusion, IFIH1 polymorphisms (rs1990760 and rs3747517) were associated with SLE susceptibility and rs1990760 risk T allele related with IL-18 and granzyme B serum levels in SLE patients.
The data support the use of IL-18, sIL-1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE.
The plasma concentration of interleukin (IL)-6, IL-18, and interferon (IFN)-α positively correlated with the expression levels of CD69 on MAIT cells in SLE.
In summary, this study identified a significant association between SLE and two SNPs within the IL-18 gene promoter region (rs360719 and rs1946518) in a European population, but not in populations of Asian origin.
For example, IL-1β and IL-18 further perpetuate Th17 responses and endothelial cell damage, which potentiate a number of autoimmune diseases, including synovitis in RA, cardiovascular disease, and systemic lupus erythematosus (SLE).
Included in this rubric is the concept that activation of the inflammasome, a molecular complex that activates caspase-1 and in turn the cytokines IL-1β and IL-18, is important in lupus pathogenesis.
This meta-analysis shows that the IL-18-607 C/A and -1297 C/T polymorphism are associated with the development of SLE in Europeans, and the IL-18-137 G/C polymorphism is associated with SLE in Asians.
For the relationship of IL-18rs1946518 polymorphism with RA (additive model: OR=0.752, 95%CI=0.562-1.006; dominant model: OR=0.730, 95%CI =0.479-1.113; recessive model: OR=0.537, 95%CI=0.271-1.064) and SLE (additive model: OR=0.684, 95%CI=0.455-1.028; dominant model: OR=0.645, 95%CI=0.368-1.130; recessive model: OR=0.672, 95%CI =0.447-1.010), no significant association with RA and SLE risk can be found under all genetic models in Asian populations.
Given that the expression of some of the p200-family proteins is differentially regulated by sex hormones and these proteins differentially regulate cytosolic DNA-induced production of type I IFN and proinflammatory cytokines (IL-1β and IL-18), the major known contributors of SLE-associated inflammation, we discuss the recent advancements in our understanding of the role of p200-family proteins in lupus susceptibility modification.
To improve the study's power, we also imputed a total of 158 SNPs across the IL18 locus using data from an SLE genome-wide association study and performed association testing.
However, there was a significant association between the IL-18 105 AA genotype (recessive model) and renal manifestations OR = 3.360 (1.523–7.415, P = 0.0039) and the P value remained statistically significant after Bonferroni correction (P corr = 0.0351).Our findings indicate that the IL-18 105 AA genotype variant can contribute to renal manifestations in patients with SLE.
Interestingly, we found the combined effect between the G/C genotype of IL-18 (-137) and the A/A genotype of IFNG (+874) gene causing susceptibility of arthritis in SLE patients (OR = 13.22, 95% CI = 1.56-291.66, P = 0.004).
The possible pathogenic role of IL-18 in lupus has been studied in a mouse model of progressive disease, which makes possible the identification, at the level of the different affected organs, of IL-18 changes preceding disease development and those appearing after disease onset.
Sequence-specific primer polymerase chain reaction and the restriction fragment length polymorphism method were used to analyse the genotypes of IL-18 promoter polymorphism at the position -607 in 101 unrelated patients with LN, 64 non-renal patients with SLE and 174 ethnically matched healthy controls.