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J. Biol. Chem., Vol. 277, Issue 19, 16879-16887, May 10, 2002
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From the Departments of 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.
Shedding of the Interleukin-6 (IL-6) Receptor (gp80)
Determines the Ability of IL-6 to Induce gp130 Phosphorylation
in Human Osteoblasts*
,,§,,¶
Orthopedic Surgery,
¶ Biochemistry, and § Immunology/Microbiology, Rush
University, Rush-Presbyterian-St. Luke's Medical Center,
Chicago, Illinois 60612
*
This work was supported in part by the National Institutes
of Health (Bethesda, MD), Zimmer Inc. (Warsaw, IN), the Musculoskeletal Research Foundation (Chicago, IL), and the Crown Family Chair of
Orthopedic Surgery and the J. O. Galante Endowed Chair
(Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Orthopedic Surgery, Rush-Presbyterian-St. Luke's Medical Center, 1653 W. Congress Pkwy., Chicago, IL 60612. Tel.: 312-942-5855; Fax: 312-942-8828; E-mail: tglant@rush.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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