Alternative splicing and proteolytic rupture contribute to the generation of soluble IL-6 receptors (sIL-6R) in rheumatoid arthritis

► Two processes of sIL-6R generation coexist in RA. ► The genetic background affects the proteolytic generation of sIL-6R. ► These data could be important for a better application of therapies targeting sIL6R. To describe the relationship between the two mechanisms involved in sIL6R generation in rheumatoid arthritis (RA). RA patients were selected from a group of subjects genotyped for the rs8192284 SNP, located at the proteolytic cleavage site of IL-6R. sIL6R and protease levels (ADAM17) were measured and the contribution of alternative splicing in the generation of sIL-6R was evaluated through qRT-PCR. Increased sIL-6R plasma levels and expression of spliced isoform generating sIL-6R are genotype dependent. ADAM17 concentrations were independent of the genotype studied. Alternative splicing and proteolytic cleavage participate in sIL-6R generation in RA. The rs8192284 polymorphism determines the sIL-6R plasma level through differential proteolytic rupture controlled by ADAM17.