title: 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.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, 35233-0005, USA. SJONES@BMG.BHS.UAB.EDU
authors.forename: S A
authors.initials: SA
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Horiuchi
authors.forename: D
authors.initials: D
authors.lastname: Novick
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: G M
authors.initials: GM
authors.lastname: Fuller
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000502:physiology; D012326:RNA Splicing; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D002118:Calcium