Alternative intronic polyadenylation generates the interleukin-6 trans-signaling inhibitor sgp130-E10.

Authors:
Jan Sommer, Christoph Garbers, Janina Wolf, Ahmad Trad, Jens M Moll, Markus Sack, Rainer Fischer, Joachim Grötzinger, Georg H Waetzig, Doreen M Floss, Jürgen Scheller
Year of publication:
2014
Volume:
289
Issue:
32
Issn:
0021-9258
Journal title abbreviated:
J BIOL CHEM
Journal title long:
JBC papers in press
Impact factor:
4.238
Abstract:
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 in intron 10 of the gp130 transcript results in a novel mRNA coding for an sgp130 protein isoform (sgp130-E10) of 70-80 kDa. The sgp130-E10 protein was expressed in vivo in human peripheral blood mononuclear cells. 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.