Shedding of the soluble IL-6 receptor is triggered by Ca2+ mobilization, while basal release is predominantly the product of differential mRNA splicing in THP-1 cells

Eur J Immunol. 1998 Nov;28(11):3514-22. doi: 10.1002/(SICI)1521-4141(199811)28:11<3514::AID-IMMU3514>3.0.CO;2-T.


The soluble IL-6 receptor (sIL-6R) is generated through either proteolytic shedding of the cognate receptor (PC-sIL-6R), or released as the product of differential mRNA splicing (DS-sIL-6R). Using monocytic THP-1 cells, we demonstrate that both mechanisms are independently regulated, and that each process contributes to sIL-6R production. Shedding of the IL-6R was activated by the Ca2+ ionophore, ionomycin, and inhibited by the TNF-alpha protease inhibitor (TAPI). In contrast, basal sIL-6R release was unaffected by Ca2+ depletion and largely insensitive to TAPI. Moreover, although IL-6R shedding was inactivated by serum starvation, non-stimulated production remained intact. Basal sIL-6R production via differential mRNA splicing was shown through the inhibitory action of brefeldin A and an enzyme-linked immunosorbent assay specific for DS-sIL-6R. Release of this isoform was unaffected by ionomycin or TAPI, indicating that Ca2+ mobilization activates PC-sIL-6R generation, but not DS-sIL-6R. The divergent control of these sIL-6R isoforms indicates that they may independently influence the inflammatory response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Line
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Protein Kinase C / physiology
  • RNA Splicing*
  • Receptors, Interleukin-6 / biosynthesis*
  • Receptors, Interleukin-6 / genetics
  • Tumor Necrosis Factor-alpha / physiology


  • Receptors, Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Protein Kinase C
  • Calcium