Interaction between interleukin-1 receptor 2 and Toll-like receptor 4, and cervical cytokines

Abstract

The objective was to assess the impact of genetic variation on cervical cytokine concentrations of interleukin (IL)-1α, IL-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), and first, to determine if these variants interact with polymorphisms in Toll-like receptor 4 (TLR4) that were previously shown to associate with pro-inflammatory cervical cytokine concentrations, and second, to determine if findings are affected by bacterial vaginosis (BV). We examined 183 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and receptors for associations with cervical cytokine levels in 188 African American and European American women. We tested for associations of gene-gene interactions between SNPs in TLR4 and cytokine gene and receptor polymorphisms with cervical pro-inflammatory cytokines. None of the single locus associations were significant after correction for multiple testing in either European Americans or African Americans. However, there were significant gene-gene interactions between IL-1R2 rs485127 and two SNPs in TLR4 (rs1554973 and rs7856729) with IL-1β after correction for multiple testing. Our study demonstrates that interactions between TLR4 and IL-1R2 are associated with cervical pro-inflammatory cytokine concentrations. These results provide important insights into the possible regulatory mechanisms of the inflammatory response in the presence and absence of microbial disorders such as BV. Additionally, the observed differences in allele frequencies between African Americans and those of European descent may partially explain population disparity in pregnancy-related phenotypes that are cytokine concentration-dependent.

Figure 1

Concentrations of box cox transformed IL-1β by TLR4 rs4851527 and either a) rs1554973 or b) rs7856729

Figure 2

Concentrations of box cox transformed IL-1β stratified by race for TLR4 rs4851527 and either a) rs1554973 or b) rs7856729

Figure 3

Cross-talk between TLR4 and IL-1 signaling pathways. Activation of TLR4 by lipopolysaccharide (LPS) initiates a signal through the Janus kinase signal transducer and activator of transcription 1 (JAK-STAT1) pathway as well as through tumor necrosis factor receptor-associated factor 6 (TRAF6). IL-1 signal transduction is initiated through the TRAF6 signaling pathway by the binding of either IL-1α or IL-1β to the IL-1R1/IL-1RAP complex. The IL-1R2/IL-1RAP complex competes for the binding of IL-1α and IL-1β and does not produce a signal when bound, therefore limiting the availability of IL-1α or IL-1β to bind to the IL-1R1/IL-1RAP complex. A dashed line indicates that other signaling molecules not shown are also involved in the pathway.