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J. Biol. Chem., Vol. 277, Issue 52, 51068-51076, December 27, 2002
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From the TSG-6 protein (the secreted product
of the tumor necrosis factor-stimulated gene-6), a hyaluronan-binding
protein comprised mainly of a Link and CUB module arranged in a
contiguous fashion, has been shown previously to be a potent inhibitor
of neutrophil migration in an in vivo model of acute
inflammation (Wisniewski, H. G., Hua, J. C., Poppers, D. M., Naime, D., Vilcek, J., and Cronstein, B. N. (1996)
J. Immunol. 156, 1609-1615). It was hypothesized that
this activity of TSG-6 was likely to be mediated by its potentiation of
inter-
The Link Module from Human TSG-6 Inhibits Neutrophil Migration in
a Hyaluronan- and Inter-
-inhibitor-independent Manner*
,,
,**, and
Department of Biochemical Pharmacology, The
William Harvey Research Institute, St. Bartholomew's and the Royal
London School of Medicine and Dentistry, London EC1M 6BQ, United
Kingdom, § Medical Research Council Immunochemistry Unit,
Department of Biochemistry, University of Oxford, South Parks Rd.,
Oxford OX1 3QU, United Kingdom, and ¶ Department of Medical
Biochemistry and Microbiology, Uppsala University,
S-751 23 Uppsala, Sweden
-inhibitor anti-plasmin activity (causing a down-regulation of
the protease network), which was reliant on these proteins forming a
stable, probably covalent ~120-kDa complex. Here we have shown that
the recombinant Link module from human TSG-6 (Link_TSG6; expressed in
Escherichia coli) has an inhibitory effect on neutrophil influx into zymosan A-stimulated murine air pouches, equivalent to that
of full-length protein (which we produced in a Drosophila expression system). The active dose of 1 µg of Link_TSG6 per mouse (administered intravenously) also resulted in a significant reduction in the concentrations of various inflammatory mediators
(i.e. tumor necrosis factor-, KC, and
prostaglandin E2) in air pouch exudates. Link_TSG6,
although unable to form a stable complex with inter--inhibitor
(under conditions that promote maximum complex formation with the
full-length protein), could potentiate its anti-plasmin activity. This
demonstrates that formation of an ~120-kDa
TSG-6·inter--inhibitor complex is not required for TSG-6 to
enhance the serine protease inhibitory activity of inter--inhibitor. Six single-site Link_TSG6 mutants (with wild-type folds) were compared
for their abilities to inhibit neutrophil migration in vivo, bind hyaluronan, and potentiate inter--inhibitor. These experiments indicate that all of the inhibitory activity of TSG-6 resides within the Link module domain, and that this anti-inflammatory property is not related to either its hyaluronan binding function or
its potentiation of the anti-plasmin activity of
inter--inhibitor.
*
This work was supported by British Heart Foundation Grant
PG/2000022 and Arthritis Research Campaign Grant M0625.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.
An Arthritis Research Campaign and Oliver Bird Fund Fellow
(grants M0621 and RHE/00045/G, respectively).
**
Recipient of Arthritis Research Campaign Fellowship P0583.
To whom correspondence should be addressed. Tel.:
44-1865-275349; Fax: 44-1865-275729; E-mail:
tony.day@bioch.ox.ac.uk.
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