Identification of a truncated splice variant of IL-18 receptor alpha in the human and rat, with evidence of wider evolutionary conservation

Abstract

Interleukin-18 (IL-18) is a pro-inflammatory cytokine which stimulates activation of the nuclear factor kappa beta (NF-κB) pathway via interaction with the IL-18 receptor. The receptor itself is formed from a dimer of two subunits, with the ligand-binding IL-18Rα subunit being encoded by the IL18R1 gene. A splice variant of murine IL18r1, which has been previously described, is formed by transcription of an unspliced intron (forming a ‘type II’ IL18r1 transcript) and is predicted to encode a receptor with a truncated intracellular domain lacking the capacity to generate downstream signalling. In order to examine the relevance of this finding to human IL-18 function, we assessed the presence of a homologous transcript by reverse transcription-polymerase chain reaction (RT-PCR) in the human and rat as another common laboratory animal. We present evidence for type II IL18R1 transcripts in both species. While the mouse and rat transcripts are predicted to encode a truncated receptor with a novel 5 amino acid C-terminal domain, the human sequence is predicted to encode a truncated protein with a novel 22 amino acid sequence bearing resemblance to the ‘Box 1’ motif of the Toll/interleukin-1 receptor (TIR) domain, in a similar fashion to the inhibitory interleukin-1 receptor 2. Given that transcripts from these three species are all formed by inclusion of homologous unspliced intronic regions, an analysis of homologous introns across a wider array of 33 species with available IL18R1 gene records was performed, which suggests similar transcripts may encode truncated type II IL-18Rα subunits in other species. This splice variant may represent a conserved evolutionary mechanism for regulating IL-18 activity.

Cytokines mapping for tissue-specific expression, eQTLs and GWAS traits

“…The iHS test, aimed at defining evidence of recent positive selection, detected selective sweeps for three tightly linked SNPs in the IL18R1 gene, which encodes a cytokine receptor from the interleukin 1 receptor family. It has been previously discussed that the conserved across evolutionary branches mechanism of regulating IL18 signaling might represent a target for selective pressure 40 . This assumption is consistent with the fact that the top IL18R1 SNP rs2001461 (iHS CEU score 4.54) was associated with the IL18R1 expression (GWAS trait P value = 3.00E−129).…”

Divergent responses to thermogenic stimuli in BAT and subcutaneous adipose tissue from interleukin 18 and interleukin 18 receptor 1-deficient mice

“…It is well established that IL18 mediates its biological effects in a variety of organ systems and cell types 9 through stepwise binding to IL18R1 and IL18RAP, and subsequent juxtaposition of the intracellular toll/interleukin-1 receptor (TIR) domains of both receptors 50 . However, additional truncated variants of IL18R1 and IL18RAP, lacking this domain essential for recruitment of MYD88 adaptor protein and subsequent activation of (NF)-ΚΒ and MAPK pathways, have been reported in humans and rodents (arbitrary named type II receptors) 10 11 51 . Though their exact role is yet to be fully established, they are proposed to act as competitors of the canonical receptors in heterodimer formation thereby inhibiting IL18 actions 10 11 .…”

The family of the interleukin‐1 receptors

“…Their function has not been clarified, and there is no information as to whether they are generated by alternative splicing or proteolytic cleavage. IL‐1R5 can undergo alternative splicings that generate soluble receptors in mice and rats and a non‐signaling membrane receptor, similar to IL‐1R2, in humans . Both sIL‐1R5 and sIL‐1R7, forming complexes with IL‐18, have been found at increased levels in the serum of patients with rheumatoid arthritis and adult‐onset Still's disease .…”

“…IL-1R5 can undergo alternative splicings that generate soluble receptors in mice and rats and a non-signaling membrane receptor, similar to IL-1R2, in humans. 380,381 Both sIL-1R5 and sIL-1R7, forming complexes with IL-18, have been found at increased levels in the serum of patients with rheumatoid arthritis and adult-onset Still's disease. 188 In mice, it has been shown that sIL-1R7 worsens experimental arthritis through upregulation of Th17 activation and concomitant downregulation of Th1, Th2, and Treg activity, 382 but whether this effect has anything to do with IL-18 inhibition is not known.…”