Alternative intronic polyadenylation generates the interleukin-6 trans-signaling inhibitor SGP130-E10 [Signal Transduction]

June 27th, 2014 by Sommer, J., Garbers, C., Wolf, J., Trad, A., Moll, J. M., Sack, M., Fischer, R., Grotzinger, J., Waetzig, G. H., Floss, D. M., Scheller, J.

Interleukin (IL)-6 signals via a receptor complex composed of the signal-transducing β-receptor gp130 and the non-signaling membrane-bound or soluble IL-6 receptor α (IL-6R, sIL-6R), which is referred to as classic and trans-signaling, respectively. IL-6 trans-signaling is functionally associated with the development of chronic inflammatory diseases and cancer. Soluble gp130 (sgp130) variants are natural inhibitors of trans-signaling. Differential splicing yields sgp130 isoforms. Here, we describe that alternative intronic polyadenylation (IPA) in intron 10 of the gp130 transcript results in a novel mRNA coding for a sgp130 protein isoform (sgp130-E10) of 70-80 kDa. The sgp130-E10 protein was expressed in vivo in human peripheral blood mononuclear cells (PBMCs). To assess the biological activity of sgp130-E10, we expressed this variant as Fc-tagged fusion protein (sgp130-E10Fc). Recombinant sgp130-E10Fc binds to a complex of IL-6 and sIL-6R, but not to IL-6 alone, and specifically inhibits IL-6 trans-signaling. Thus, it might play an important role in the regulation of trans-signaling in vivo.