IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

Abstract

The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4 þ T-helper 17 (Th 17 ) cells, whereas IL-12 negates IL-17A production by promoting Th 1 -cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml --1 vs 176.11 ± 277.32 pg ml --1 ; P ¼ 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.

Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review

“…Those results suggest that IL-23 receptor AA genotype variant of rs11209026 would contribute to RA etiology; consequently, it might be a genetic marker for RA. Another study reported that a R381Q polymorphism modulated IL-17A expression in patients with RA (Hazlett et al 2012). Those authors suggested that, in patients with the 381Gln allele, higher IL-23 concentrations might have been needed to produce IL-17A concentrations similar to those in patients with a 381Arg allele.…”

cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

“…This could be a reflection of diverse pathomechanisms in SLE and RA. The up-regulation of IL-17A together with unaltered IL-2 expression in RA could be a result of increased Stat3 activation through IL-6 or attenuated IL-23 receptor signaling in the absence of increased CREMα expression (20). (iii) We document a mechanism that contributes to T-cell lineage determination and an enrichment of effector memory phenotypes in SLE.…”

“…Thus, we examined the mRNA expression of CREMα, IL-2 and IL-17A, and CpG-DNA methylation of the promoters of CREM, IL2, and IL17A in T cells from SLE patients with active (SLEDAI: 8-14) and inactive (SLEDAI: 0-4) disease vs. age-, sex-, and ethnicity-matched healthy controls (Table S1). Because patients with RA produce increased levels of proinflammatory cytokines, including IL-2 (5,19,20), we included T cells from RA patients with active disease in our study (Table S2, Fig. S4).…”

Association between lower frequency of R381Q variant (rs11209026) in IL-23 receptor gene and increased risk of recurrent spontaneous abortion (RSA)

“…Some studies also indicated that the A allele frequency of R381Q was lower in ankylosing spondylitis (AS) patients than in healthy controls (Duan et al, 2012;Rahman et al, 2008). Another study indicated that a R381Q polymorphism modulated IL-17A expression in patients with rheumatoid arthritis (Hazlett et al, 2012). Those authors suggest that, in patients with the 381Gln allele, higher IL-23 concentrations may be needed to produce IL-17A concentrations similar to those in patients with the 381Arg allele.…”