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Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts
Journal article   Open access   Peer reviewed

Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts

Csaba Vermes, Joshua J Jacobs, Jian Zhang, Gabor Firneisz, Kenneth A Roebuck and Tibor T Glant
The Journal of biological chemistry, Vol.277(19), pp.16879-16887
05/10/2002
DOI: 10.1074/jbc.M200546200
PMID: 11884403
url
https://doi.org/10.1074/jbc.M200546200View
Published (Version of record) Open Access

Abstract

Human osteoblasts produce interleukin-6 (IL-6) and respond to IL-6 in the presence of soluble IL-6 receptor (sIL-6R), but the cell surface expression of IL-6R and the mechanism of sIL-6R production are largely unknown. Three different human osteoblast-like cell lines (MG-63, HOS, and SaOS-2) and bone marrow-derived primary human osteoblasts expressed both IL-6R and gp130 as determined by flow cytometry and immunoprecipitation. However, the membrane-bound IL-6R was nonfunctional, as significant tyrosine phosphorylation of gp130 did not occur in the presence of IL-6. Phorbol myristate acetate induced a dramatic increase of both IL-6R shedding (i.e. the production of sIL-6R) and IL-6 release in osteoblast cultures, but the cell surface expression of gp130 remained unchanged. IL-6 complexed with sIL-6R, either exogenously introduced or derived from the nonfunctional cell surface form by shedding, induced rapid tyrosine phosphorylation of gp130. This effect was inhibited by neutralizing antibodies to either sIL-6R or gp130, indicating that the gp130 activation was induced by IL-6/sIL-6R/gp130 interaction. Protein kinase C inhibitors blocked phorbol myristate acetate-induced and spontaneous shedding of IL-6R resulting in the absence of sIL-6R in the culture medium, which in turn also prevented the activation of gp130. In conclusion, human osteoblasts express cell surface IL-6R, which is unable to transmit IL-6-induced signals until it is shed into its soluble form. This unique mechanism provides the flexibility for osteoblasts to control their own responsiveness to IL-6 via the activation of an IL-6R sheddase, resulting in an immediate production of functionally active osteoblast-derived sIL-6R.
 Phosphorylation Membrane Glycoproteins - metabolism Humans Molecular Sequence Data Antigens, CD - metabolism Membrane Glycoproteins - physiology Flow Cytometry Time Factors Base Sequence Transcription, Genetic Cell Membrane - metabolism Protein Synthesis Inhibitors - pharmacology Interleukin-6 - metabolism Cytokine Receptor gp130 Cell Survival Cells, Cultured Enzyme Inhibitors - pharmacology Glycosylation Reverse Transcriptase Polymerase Chain Reaction Blotting, Western Precipitin Tests Receptors, Interleukin-6 - physiology Tyrosine - metabolism Antigens, CD - physiology Osteoblasts - metabolism Receptors, Interleukin-6 - metabolism

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