MRC Immunochemistry Unit, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, UK
* Author for correspondence (e-mail: tony.day{at}bioch.ox.ac.uk)
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Summary |
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Key words: TSG-6, Hyaluronan, Inter--inhibitor, Ovulation, Inflammation, Arthritis
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Introduction |
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Properties and functions of TSG-6 |
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The function of the CUB module of TSG-6 remains unknown, although the fact
that it is highly conserved between species suggests that it is essential for
at least some activities of TSG-6. This module occurs in a wide range of
proteins many of which are involved in fertilisation and development
(Bork and Beckmann, 1993)
for example the spermadhesins
(Romero et al., 1997
) and the
tolloid metalloproteinases (Scott et al.,
1999
). It is also found in the complement serine proteinases C1r,
C1s, MASP1, MASP2 and MASP3 (Sim and
Laich, 2000
). In these contexts, CUB modules bind both protein and
carbohydrate ligands, including heparin, members of the TGFb superfamily,
collagen and collagen-like proteins (see also
http://smart.embl-heidelberg.de:8080/smart/do_annotation.pl?DOMAIN=CUB).
Hulmes et al. have reported that procollagen C-proteinase enhancer promotes
tolloid proteinase activity and thereby controls collagen assembly through its
two CUB modules (Hulmes et al.,
1997
).
The structure of the TSG-6 CUB module (see
Fig. 3) has been modelled
(Nentwich et al., 2002) on the
basis of the coordinates from three spermadhesins, each comprising a single
CUB module that has a structure related to a jellyroll fold
(Romão et al., 1997
;
Varela et al., 1997
). Two
allelic variants of TSG-6 exist owing to a G/A dimorphism at nucleotide 431,
which results in an Arg/Gln alteration in the CUB module (residue 144 of the
preprotein) (Nentwich et al.,
2002
). The newly described Gln144 allotype is the most
common in Caucasians (>75% are A431 homozygotes), but as yet no
functional differences have been identified between the two TSG-6 variants
when they are expressed in Drosophila cells
(Nentwich et al., 2002
;
Getting et al., 2002
).
Regulation of TSG-6 expression
Although there is little or no constitutive expression of TSG-6 in
unstimulated cells or tissues, it is produced in response to a wide range of
factors (see Table 1). The
rapid upregulation of TSG-6 in the presence of the pro-inflammatory cytokines
TNF and IL-1 is consistent with its involvement in inflammatory processes.
Indeed, high levels of TSG-6 protein have been detected in the sera from
patients who have bacterial sepsis and systemic lupus erythematosus
(Lee et al., 1993b;
Wisniewski and Vilcek, 1997
),
in mucosal smooth muscle cells (mSMCs) from individuals who have inflammatory
bowel disease (C. A. de la Motte, V. C. Hascall, A.J.D. and S. A. Strong,
unpublished) and in the joint tissues and synovial fluids (and to a lesser
extent the sera) of patients who have various forms of arthritis
(Wisniewski et al., 1993
;
Lee et al., 1993b
;
Bayliss et al., 2001
) (see
Fig. 1). TSG-6 mRNA and protein
are also produced in cumulus oocyte complexes (COCs) following the induction
of ovulation (Fülöp et al.,
1997
; Yoshioka et al.,
2000
; Carrette et al.,
2001
; Mukhopadhyay et al.,
2001
) and by cervical SMCs (cSMCs) treated with PGE2,
which promotes cervical ripening (Fujimoto
et al., 2002
): both of these processes can be classed as
inflammation-like. TSG-6 is expressed in several cell types, including
chondrocytes, synoviocytes and vascular SMCs (vSMCs), in response to various
growth factors (see Table 1).
For example, TGFß, FGF and EGF induce TSG-6 production in rabbit vSMCs
and overexpression of TSG-6 causes an increase in cell proliferation of
>50% (Feng and Liau, 1993
;
Ye et al., 1997
). Ye et al.
have detected high levels of TSG-6 in proliferating SMCs in the neointima
following balloon catheter injury of rat blood vessels, suggesting that it
might be involved in the response to vascular injury
(Ye et al., 1997
). A recent
study, using microarray technology, identified TSG-6 as one of a very
small number of genes upregulated (
four-fold) in human arterial SMCs in
response to mechanical strain (Feng et
al., 1999
; Lee et al.,
2001
). These conditions also differentially modulated the
synthesis of vascular proteoglycans (resulting in elevated levels of versican,
biglycan and perlecan and reduced levels of decorin) and caused increased
aggregation of versican with HA (Lee et
al., 2001
). Following a biomechanical stimulus, the arterial ECM
thus appears to undergo a highly coordinated reorganisation in which TSG-6
might participate.
TSG-6 expression is differentially regulated depending on the cell type
(Table 1). For example,
although IL-1 and TNF are strong inducers of TSG-6 expression in many cell
types, IL-1 has no such effect on peripheral blood monocytes (PBMCs) and vSMCs
are unresponsive to TNF. Furthermore, among the cell types and stimuli tested,
there is considerable variation in the kinetics of TSG-6 production and its
sensitivity to protein synthesis inhibitors. This suggests that several
distinct pathways regulate TSG-6 expression. For example, cycloheximide does
not inhibit TSG-6 transcription in response to TNF, IL-1 or
PGE2 (Feng and Liau,
1993; Lee et al.,
1993a
; Fujimoto et al.,
2002
) but abrogates growth-factor-induced expression of
TSG-6 (Feng and Liau,
1993
; Ye et al.,
1997
). Furthermore, although the upregulation of TSG-6 in
response to most stimuli is rapid and relatively short lived, some factors
[e.g. TGFß (Feng and Liau,
1993
; Maier et al.,
1996
) and PGE2
(Fujimoto et al., 2002
)]
invoke a delayed and more prolonged response. Studies of the TSG-6
promoter have identified NF-IL6 and AP-1 sites as being amongst the elements
involved in the regulation of both TNF- and IL-1-induced TSG-6
expression, although these cytokines are not thought to act through identical
pathways (Lee et al., 1993a
;
Klampfer et al., 1994
;
Wisniewski and Vilcek, 1997
).
PGE2 probably targets different regulatory elements
(Fujimoto et al., 2002
).
Recent studies employing DNA microarray technology and/or proteomics have
revealed novel sites of TSG-6 expression (see
Table 1). For example,
constitutive expression of TSG-6 mRNA is 5.3-fold higher in gingival
fibroblasts compared with periodontal ligament fibroblasts
(Han and Amar, 2002). This
could be significant, since gingival and periodontal ligament fibroblasts
display distinct activities during the maintenance of tissue integrity and in
inflammatory disease, which may result from the differential expression of
specific genes. Microarray analysis has also identified a significant number
of distinct genes as being induced or repressed in neutrophils after a 4 hour
incubation with LPS: TSG-6 mRNA was increased up to 7.1-fold in this
context (Fessler et al., 2002
;
Malcolm et al., 2003
).
Similarly, TSG-6 is one of 28 mRNAs upregulated during TNF-driven
maturation of monocyte-derived dendritic cells
(Le Naour et al., 2001
).
Mikita et al. used microarray technology to identify 127 genes upregulated
following LPS treatment of human THP-1-derived macrophages
(Mikita et al., 2001
). In this
case TSG-6 mRNA was upregulated 5.9-fold 1 hour after LPS treatment
and 8.9-fold after 6 hours. However, this effect was delayed in lipid-loaded
macrophages, which exhibit a phenotype similar to that of the foam cell
macrophages believed to play a major role in the pathology of atherosclerosis.
Infection with the intracellular pathogen Chlamydia pneumoniae causes
acute respiratory illnesses, such as pneumonia and bronchitis, and has been
implicated in chronic conditions including atherosclerosis and coronary heart
disease in humans. TSG-6 is one of
20 genes that are
significantly upregulated (
two-fold induction) in C.
pneumoniae-infected human microvascular endothelial cells
(Coombes and Mahony, 2001
),
which suggests that it might be involved in the pathology of vascular and
respiratory diseases.
Reversible and irreversible p53-mediated G1 cell cycle arrest
can be induced in human fibroblasts by the antimetabolite
N-phosphoacetyl-L-aspartate (PALA) and -irradiation,
respectively. cDNA representational difference analysis has revealed that
TSG-6 mRNA is substantially upregulated in embryonic skin fibroblasts
by PALA, but not
-irradiation, indicating that TSG-6 might be a novel
component of the reversible arrest pathway
(Seidita et al., 2000
).
Furthermore, the absence of TSG-6 expression in p53-defective cells
suggests that TSG-6 is directly controlled by p53.
p21WAF1/CIP1 is a downstream effector in p53-mediated
G1 arrest, but can also be upregulated and drive apoptosis in a
p53-independent manner. Wu et al. have used adenovirus-vector-mediated
transduction of p53 (rAd-p53) or p21WAF1/CIP1 (rAd-p21) to
mimic p53-dependent and -independent upregulation, respectively, of
p21WAF1/CIP1 in human ovarian cancer cell lines
(Wu et al., 2002
).
TSG-6 is not induced by rAd-p53 but is significantly upregulated
within 4-8 hours of rAd-p21 infection. p53-independent apoptosis might thus be
another process in which TSG-6 functions.
TSG-6 and inter--inhibitor
The first detailed study of TSG-6 expression
(Lee et al., 1992) detected an
120 kDa TSG-6-immunoreactive species in the culture supernatants of
TNF-stimulated fibroblasts in addition to the expected
35 kDa protein.
Analysis of recombinant human (rh)TSG-6 expressed using baculovirus revealed
that this 120 kDa species is a stable, probably covalent, complex comprising
TSG-6 and a serum protein (Wisniewski et
al., 1992
). The latter was identified as I
I, one of a
family of closely related serine protease inhibitors
(Wisniewski et al., 1994
).
I
I consists of three polypeptides [heavy chain 1 (HC1), heavy chain 2
(HC2) and bikunin] linked by a chondroitin sulphate moiety that originates
from a glycosidic linkage to Ser-10 of bikunin
(Enghild et al., 1999
); it is
the bikunin component that is responsible for the protease inhibitory effects
of I
I. Co-incubation of I
I purified from human serum with
rhTSG-6 gave rise to a 120 kDa complex, and microsequencing of this
chondroitinase ABC-sensitive species revealed the presence of TSG-6 together
with bikunin and HC2 (Wisniewski et al.,
1994
). Although they noted that the total mass of these components
is greater than 120 kDa, Wisniewski et al. hypothesised that TSG-6 replaces
HC1 of I
I in a transesterification reaction
(Wisniewski et al., 1994
).
TSG-6II complexes have been seen in physiological samples,
indicating that they do occur in vivo. Wisniewski et al. detected a 120 kDa
TSG-6I
I complex in the synovial fluids of arthritic patients
(Wisniewski et al., 1993
;
Wisniewski et al., 1994
),
which was assumed to have the composition detailed above (i.e. TSG-6, HC2 and
bikunin linked by chondroitin sulphate), although this was not shown
experimentally. In contrast, Mukhopadhyay et al. have identified a
125
kDa TSG-6I
I complex
(Mukhopadhyay et al., 2001
),
which was insensitive to chondroitinase ABC, in the ECM of ovulated COCs from
murine fallopian tubes. Mass spectrometry of peptides derived from this
species indicated that it contains TSG-6, HC1 and HC2 (but no bikunin) and
probably represents two complexes, HC1·TSG-6 and HC2·TSG-6,
because TSG-6 has a molecular weight of
35 kDa and each of the heavy
chains is
83 kDa. These complexes are sensitive to mild NaOH treatment
and, thus, might contain ester linkages. Nentwich et al. showed that rhTSG-6
expressed by Drosophila cells and I
I purified from human serum
form an
120 kDa complex after just 30 seconds at 37°C
(Nentwich et al., 2002
).
Furthermore, this complex has the same composition as that detected in murine
COCs (M. S. Rugg, A. C. Willis, E. Fries and A.J.D., unpublished data).
Colocalisation of TSG-6 and I
I in vivo is, therefore, likely to give
rise to rapid complex formation. However, it seems possible that several
covalent TSG-6·I
I complexes, which have different compositions
and structures, might exist.
II, like TSG-6, is a HA-binding protein: this was first reported by
Sandson et al., who found that HA recovered from pathological synovial fluids
is tightly bound to I
I (Sandson et
al., 1965
). More recent studies have shown that the heavy chains
of I
I (HC1 and HC2) and heavy chain 3 (HC3) from the related protein
pre-
-inhibitor (P
I) (which are collectively termed serum-derived
HA-associated proteins or SHAPs) can form covalent complexes with HA, probably
owing to substitution of chondroitin sulphate by HA in transesterification
reactions (Yoneda et al.,
1990
; Huang et al.,
1993
; Zhao et al.,
1995
); isolated HA and I
I do not interact covalently,
indicating that a serum factor catalyses this process (Haung et al., 1993). HA
acts as a vital structural component of connective tissues as well as
contributing to processes such as immune cell trafficking and intracellular
signalling (Tammi et al.,
2002
). Its synthesis is upregulated by TNF and IL-1 and its levels
are elevated in the joints of patients with rheumatoid arthritis (RA)
(Hamerman and Wood, 1984
;
Butler et al., 1988
). I
I
is barely detectable in normal synovial fluids but occurs at elevated levels
in disease [probably originating from serum
(Becker and Sandson, 1971
)],
and high levels of SHAPs have been detected in osteoarthritis (OA) and RA
synovial fluids (Kida et al.,
1999
). The ability of TSG-6 to interact with both HA and
I
I, and its upregulation in inflammatory situations, suggests that it
might somehow influence the formation of HA·I
I complexes and
thus be important for regulating ECM remodelling and/or assembly.
As mentioned above, II is a protease inhibitor, but although it is
present in human serum at
0.45 mg/ml and has been reported to inactivate
a broad range of serine proteases (including trypsin, neutrophil elastase and
plasmin), its activity is relatively low and its physiological relevance in
this regard is not clear (Potempa et al.,
1989
; Salier et al.,
1996
). Wisniewski et al. used an in vitro plasmin assay to show
that the very modest anti-plasmin activity of I
I is potentiated by
TSG-6 (which alone has virtually no effect on plasmin)
(Wisniewski et al., 1996
),
although TSG-6 does not modulate the inhibition of other proteases (trypsin,
neutrophil elastase and urokinase) by I
I. Janssen et al. have found
that stimulation of TSG-6 expression in renal epithelial cells (which
constitutively produce the components of P
I, i.e. bikunin and HC3)
reduces plasmin activity in culture supernatants, an effect that is abolished
by TSG-6 immunoprecipitation (Janssen et
al., 2001
). Recently, we have shown that recombinant Link_TSG6
alone can potentiate the anti-plasmin activity of I
I, although it
cannot form a covalent complex with I
I
(Getting et al., 2002
).
Therefore, covalent complex formation is not necessary for TSG-6 to modulate
I
I activity. Furthermore, the TSG-6·I
I complexes that we
have characterised (Mukhopadhyay et al.,
2001
) (M. S. Rugg, A. C. Willis, E. Fries and A.J.D., unpublished
data) do not contain the bikunin chain and, therefore, would not be expected
to exhibit any serine protease inhibitory activity.
TSG-6 thus appears to influence II at two different levels (see
Fig. 2). Firstly, through the
formation of one or more type of covalent complex with I
I, TSG-6 might
somehow contribute to the formation of I
I·HA complexes in the
ECM. Secondly, as a result of non-covalent interactions, TSG-6 enhances the
anti-plasmin activity of I
I and thus might modulate the protease
network. This could have significant physiological relevance during
inflammatory processes, in which ECM remodelling and the regulation of
protease activity are key features.
TSG-6 in arthritis
Given that TSG-6 levels are elevated in the synovial fluids, and to a
lesser extent the sera, of patients who have various forms of arthritis
(Wisniewski et al., 1993), how
might it influence these conditions? TSG-6 expression can be induced in
cultured articular synoviocytes by IL-1 and TNF
(Wisniewski et al., 1993
) and
in articular chondrocytes by IL-1, TNF, PDGF and TGFß
(Maier et al., 1996
;
Margerie et al., 1997
). There
is also good evidence that TSG-6 is produced locally in the synovium and
cartilage of OA and RA joints (Bayliss et
al., 2001
). For example, TSG-6 has been detected in the blood
vessel walls of inflamed synovium and within the pannus region of patients
with arthritis. Its presence in these locations is consistent with the
involvement of TSG-6 in cell proliferation
(Ye et al., 1997
) and/or ECM
remodelling. Indeed, TSG-6 expression is upregulated in the ECM surrounding
OA-like lesions in STR/ort mice (which develop a natural form of OA),
decreased levels of aggrecan being detected in areas strongly expressing TSG-6
(Flannelly et al., 2001
).
TSG-6 might, therefore, compete with aggrecan for binding to HA in vivo as it
does in vitro (Parkar et al.,
1998
). Furthermore TSG-6 is detectable in the chondrocyte
pericellular matrix of young STR/ort mice, prior to the development of OA
lesions and, thus, may be an early marker for disease.
Mapping to human chromosome 2q23.3, TSG-6 lies within the 2q12-q35
region identified as harbouring an OA susceptibility locus [Nentwich et al.
(Nentwich et al., 2002) and
references therein]. Nentwich et al. have, therefore, typed panels of 400 OA
patients and 400 controls for the TSG-6 G431A single nucleotide
polymorphism described above (Nentwich et
al., 2002
). Although this dimorphism did not prove to be a marker
for OA in the population studied, this does not rule out the possibility that
other, as-yet-unidentified, variants of TSG-6 contribute to OA
susceptibility.
Several mouse models have been used to investigate the role(s) of TSG-6 in
arthritis. Collagen-induced arthritis (CIA) is an autoimmune polyarthritis
inducible in susceptible mouse strains by immunisation with type II collagen
and has a histopathology similar to that of human RA, including synovitis,
followed by cartilage destruction and bone erosion with eventual loss of joint
function. Mindrescu et al. have used this model to test the effects of
systemic recombinant TSG-6 and of TSG-6 produced locally by T cells in the
arthritic joints of transgenic mice
(Mindrescu et al., 2000;
Mindrescu et al., 2002
). Both
approaches reduced disease incidence and caused potent inhibition of
inflammation and joint destruction. The transgenic mice showed the greater
amelioration (as well as delayed onset) of symptoms, and the improvement was
comparable to that seen with anti-TNF antibody treatment. Local expression of
TSG-6 in arthritic joints could, therefore, limit inflammation and thereby
protect cartilage and bone. Note that, although treatment of CIA-affected mice
with rhTSG-6 caused significant reduction in the levels of antibodies against
type II collagen, no such effect was seen in the TSG-6 transgenic
mice, which suggests that TSG-6 does not affect the immune response to type II
collagen. This idea is supported by the fact that there is no evidence for
altered cytokine production or inhibition of T cell activity in response to
type II collagen in TSG-6 transgenic mice with CIA
(Mindrescu et al., 2002
).
Bárdos et al. have used mice with protoeglycan-induced arthritis
(PGIA) as a model for human RA to determine the effects of systemic TSG-6
administration (Bárdos et al.,
2001). Intravenous injection of severely arthritic mice with
recombinant murine TSG-6 (rmTSG-6) caused a dramatic reduction in joint edema
and, in long-term treatment, inhibited cartilage degradation and bone erosion.
However, it did not delay the onset or reduce the incidence of PGIA nor did it
alter the production of various pro- and anti-inflammatory cytokines, the
levels of antibodies to PGs or PG-specific T cell responses.
CD44 is the major cell surface receptor for HA
(Tammi et al., 2002), and
CD44-HA interactions contribute to leukocyte rolling during inflammation
(Mohamadzadeh et al., 1998
;
Puré and Cuff, 2001
).
Pro-inflammatory cytokines upregulate HA expression on the vascular
endothelium and induce the HA-binding capacity of CD44+ leukocytes,
thereby promoting the contribution of HA-CD44 interactions to leukocyte
migration. Since TSG-6 also binds HA, TSG-6 might mediate its
anti-inflammatory effects by blocking this interaction. However, Mindrescu et
al. saw no correlation between the extent of T lymphocyte infiltration into
the joints of TSG-6 transgenic mice with CIA and the severity of disease
(Mindrescu et al., 2002
), and
Bárdos et al. observed that although TSG-6 can compete with CD44 for
binding to HA in vitro (albeit at very high TSG-6 concentrations), this does
not appear to be the case in vivo
(Bárdos et al., 2001
).
These data suggest that the anti-inflammatory effect of TSG-6 in arthritis is
unlikely to be due entirely to inhibition of T lymphocyte influx, although
this could be a contributory mechanism. Moreover, recent work has shown that
pre-incubation of HA with TSG-6 or Link_TSG6 enhances and/or induces the
binding of CD44+ cells to HA, both under static and flow
conditions, which suggests that TSG-6 promotes lymphocyte adhesion/migration
(J. Lesley, K. Mikecz and A.J.D., unpublished).
Bárdos et al. also observed that a single intra-articular injection
of rmTSG-6 into the acutely inflamed joints of mice with antigen-induced
arthritis (AIA; a model for monoarticular arthritis) has a strong
chondroprotective effect, which lasts for 5 to 7 days
(Bárdos et al., 2001).
The absence of aggrecan fragments from treated joints indicated that the
matrix metalloproteinases (MMPs) that degrade cartilage proteoglycans under
inflammatory conditions were inhibited. To investigate the chondroprotective
effect, Glant et al. generated transgenic mice that express murine TSG-6
specifically in cartilage (Glant et al.,
2002
). The induction of AIA in these mice results in severe joint
inflammation, but their cartilage remains intact for at least 1 week (control
mice suffered major damage from day 5) and both loss of aggrecan and
accumulation of MMP-generated fragments are reduced. Furthermore, after 4-5
weeks, TSG-6 transgenic mice are free of local inflammation and their
cartilage is almost fully repaired (which is not the case in controls). Glant
et al. hypothesise that potentiation of the anti-plasmin effect of I
I
by TSG-6 is responsible (Glant et al.,
2002
), as plasmin is involved in the activation of cartilage MMPs,
which have matrix-degrading activity (MMPs 1, 2, 3, 9 and 14) (reviewed in
Murphy et al., 1999
), and can
also participate in the activation of aggrecanases [Glant et al.
(Glant et al., 2002
) and
references therein]. Bárdos et al. observed that TSG-6 injected into
mice accumulates at sites of inflammation (probably by binding HA)
(Bárdos et al., 2001
),
which would allow it to entrap I
I from the serum. In this regard, both
TSG-6I
I and HA·I
I complexes have been detected in
the synovial fluids of patients who have arthritis
(Becker and Sandson, 1971
;
Wisniewski et al., 1993
),
although the roles of these species are not clear.
TSG-6 as a regulator of inflammation
The importance of the plasmin/plasminogen activator system in regulating
the protease network associated with inflammation led Wisniewski et al. to
investigate the effect of TSG-6 on a mouse air pouch model of acute
inflammation (Wisniewski et al.,
1996). The cells lining an air pouch resemble those in the
synovial lining of a joint, and the introduction of a proinflammatory stimulus
(e.g. carrageenan or IL-1) produces local effects similar to synovitis.
Co-injection of rhTSG-6 significantly reduces neutrophil infiltration.
Wisniewski et al. detected a 120 kDa, TSG-6-immunoreactive species
(Wisniewski et al., 1996
),
assumed to be the TSG-6I
I complex described previously
(Wisniewski et al., 1994
), in
air pouch exudates and found that two single-site mutants of rhTSG-6 that
exhibited little or no potentiation of the anti-plasmin effect of I
I
(although they formed stable TSG-6I
I complexes) showed reduced
or no anti-inflammatory activity. This led them to hypothesise that TSG-6
inhibits neutrophil migration by modulating the protease network in
conjunction with I
I.
Recent work has revealed that the anti-inflammatory effect of TSG-6 is
mediated by its Link module (Getting et
al., 2002). In mouse air pouch models of IL-1- or zymosan-induced
acute inflammation, equivalent doses of rhTSG-6 and Link_TSG6 inhibit
neutrophil influx to similar extents. Link_TSG6 also significantly reduces
levels of the inflammatory mediators KC, TNF and PGE2 in air pouch
exudates. Analysis of Link_TSG6 mutants revealed that the anti-inflammatory
effects of TSG-6 in vivo are likely to be independent of its ability to bind
HA or potentiate I
I action (Getting
et al., 2002
). This study, therefore, casts doubt on the
hypothesis that the anti-inflammatory effect of TSG-6 is mediated through
downregulation of the protease network. We also observed that Link_TSG6 exerts
similar neutrophil-inhibitory effects in different models of inflammation and
regardless of its route of administration (i.e. into the inflammatory site or
intravenously). It thus seems likely that TSG-6 acts via the circulation to
influence a fundamental process of neutrophil extravasation. Preliminary
evidence suggests that TSG-6 modulates the adhesion of neutrophils to the
endothelium (Cao et al., 2002
).
The timely resolution of leukocyte extravasation is essential to prevent
damage to healthy tissue (e.g. by the toxic enzymes and free radicals released
by neutrophils), and this depends on the activation of localised
anti-inflammatory systems (Perretti,
1997
). Whatever its precise mechanism of action, it seems likely
that TSG-6 is an endogenous inhibitor of inflammation that forms part of a
negative feedback loop.
TSG-6 in ovulation
Mammalian ovulation is a highly regulated, inflammation-like process
promoted by the midcycle luteinising hormone (LH) surge and dependent on the
temporal and spatial expression of specific genes (reviewed in
Richards et al., 2002).
Ovulation is initiated in a responsive preovulatory follicle, which comprises
several layers of granulosa cells lining a central cavity that contains the
COC (an oocyte surrounded by closely adherent cumulus cells) and follicular
fluid. Upon ovulatory stimulation the compact COC expands, and this is
accompanied by permeabilisation of the blood/follicle barrier, allowing
ingress of large serum proteins. Ultimately, the expanded COC is released
through the ruptured follicle wall and enters the oviduct. The ovulatory
process has been studied in detail in mice, where it can be initiated, for
example, by administration of follicle-stimulating hormone (FSH) or human
chorionic gonadotropin (hCG; which is functionally analogous to LH).
In mice, ovulation occurs 14 hours after a LH surge, and during this
time the COC undergoes a 20- to 40-fold increase in volume
(Chen et al., 1990
) owing to
the formation of an extensive mucoelastic matrix between the cumulus cells of
the COC; this is necessary for successful ovulation and fertilisation
(Chen et al., 1993
). The major
component of the cumulus ECM (cECM) is HA, which is produced by the cumulus
and granulosa cells (Eppig,
1979
; Chen et al.,
1990
; Salustri et al.,
1992
) (reviewed by Salustri
and Fülöp, 1998
;
Richards et al., 2002
).
However, additional molecules are required for effective incorporation of
newly synthesised HA into the cECM. In particular, serum is essential for this
process because it contains I
I, which diffuses into the follicular
fluid during ovulation and is critical for organising and stabilising the
expanding matrix (Chen et al.,
1992
; Camaioni et al.,
1993
). The heavy chains of I
I can bind to HA both
covalently, as discussed above (Yoneda et
al., 1990
; Huang et al.,
1993
; Zhao et al.,
1995
), and non-covalently
(Chen et al., 1994
) and could
thereby crosslink HA chains. Furthermore, intravenous administration of HA
oligosaccharides decreases the amount of I
I incorporated into the cECM
in vivo, leading to impaired ovulation and development of mouse oocytes
(Hess et al., 1999
). More
recently, inactivation of the bikunin gene in mice has been shown to
severely impair female fertility (Sato et
al., 2001
; Zhuo et al.,
2001
). Bikunin is essential for the biosynthesis of I
I
family members, and bikunin/ female mice,
although healthy and able to maintain pregnancy
(Sato et al., 2001
), are
infertile and exhibit impaired ovulation with failed COC expansion. Zhuo et
al. attributed these defects to the absence of HC·HA complexes in
bikunin/ mice
(Zhuo et al., 2001
), and
showed that administration of purified I
I resulted in HC·HA
formation and restored the phenotype of the knockout mice to normal. However,
mixing of purified I
I and HA in vitro does not result in covalent
transfer of HCs to HA (Ødum et al.,
2002
); a factor secreted by granulosa cells has been shown to
catalyse this process (Chen et al.,
1996
). Ødum et al. speculated that this could be TSG-6
(Ødum et al., 2002
).
Although it has been suggested that such a catalytic factor may also be
present in serum (Huang et al.,
1993
; Zhuo et al.,
2001
), Ødum et al. have reported that the coupling of HA
and I
I is catalysed by follicular fluid, but not by serum.
Among the genes upon which expansion of the COC depends are HAS-2,
which upregulates HA production (Weigel et
al., 1997), TSG-6
(Fülöp et al., 1997
;
Mukhopadhyay et al., 2001
) and
COX-2, which regulates the synthesis of prostaglandins such as
PGE2 (Sirois et al.,
1992
). TSG-6 mRNA expression in expanding COCs reaches a
maximal level
3 to 4 hours after hCG administration, and the time-course
of HAS-2 mRNA appearance is similar to this
(Fülöp et al., 1997
;
Yoshioka et al., 2000
;
Mukhopadhyay et al., 2001
).
TSG-6 and HA synthesis might, therefore, be upregulated in concert to coincide
with I
I accumulation in the pre-ovulatory follicle. Recent studies have
revealed that mice lacking COX-2 or EP2 (a PGE2
receptor present on cumulus cells) exhibit impaired ovulation and COC
expansion (Davis et al., 1999
;
Kennedy et al., 1999
;
Tilley et al., 1999
).
Furthermore, a reduction in TSG-6 (but not HAS-2) mRNA
levels in the cumulus cells of these mice indicates that PGE2
regulates TSG-6 expression within the COC and led Ocshner et al. to
suggest that TSG-6 might play an essential role in the formation or function
of the cECM (Ocshner et al.,
2003
). Varani et al. have shown that growth differentiation factor
9 (GDF-9), a member of the TGFß superfamily secreted by oocytes,
upregulates the expression of COX-2, HAS-2, pentraxin 3
(Ptx3) and TSG-6 (Varani
et al., 2002
). GDF-9-knockout mice are infertile, whereas
mice null for Ptx3 exhibit female subfertility
(Elvin et al., 1999
;
Varani et al., 2002
).
TSG-6 protein is present in the cECM, where it colocalises with HA and
II; TSG-6 occurs both as a free protein and in complexes with I
I
(Carrette et al., 2001
;
Mukhopadhyay et al., 2001
).
The HC1·TSG-6 and HC2·TSG-6 complexes identified in the COC (see
above) form interactions with HA that are resistant to detergent, heat and
reducing agents but are disrupted by treatment with NaOH
(Mukhopadhyay et al., 2001
).
Given their likely covalent association with HA, these complexes might be
involved in crosslinking of HA chains, through HA binding to the TSG-6 Link
module. They could thus participate in matrix assembly within the COC. The
free TSG-6 detected in the cECM could associate non-covalently with HA and/or
intact or bikunin-containing fragments of I
I. Note that, in addition to
matrix expansion, ovulation involves regulated matrix degradation, which
results in rupture of the follicle at the surface of the ovary to allow
release of the COC into the oviduct. Various metalloproteinases and cathepsins
have been implicated in this process (reviewed in
Richards et al., 2002
), and
TSG-6 in association with I
I might regulate protease activity in this
context.
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Conclusion/perspectives |
---|
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---|
We now know that the ability of TSG-6 to potentiate the anti-plasmin
activity of II is due to the non-covalent association of these
proteins. Again, the nature of the complex formed and the mechanism(s)
involved remain to be elucidated, as does its physiological relevance. There
is evidence that the chondroprotective effect of TSG-6 in arthritis is due to
its inhibition of MMPs and aggrecanase enzymes that damage cartilage, although
further work is required to confirm whether this is via its effect on plasmin
activity. However, downregulation of the protease network does not appear to
account for the ability of TSG-6 to act as a potent inhibitor of acute
inflammation: this probably occurs via a mechanism that involves neither
I
I nor HA. Future research will focus on the influence of TSG-6 on the
interactions that contribute to leukocyte migration. Indeed, it has been shown
recently that TSG-6 enhances the interaction of HA with CD44 on the surface of
lymphocyte cell lines and thus may differentially modulate the
adhesion/migration of specific leukocyte subpopulations (J. Lesley, K. Mikecz
and A.J.D., unpublished data).
To date, all the properties of TSG-6 that have been studied in detail can be attributed to its Link module, and research into the role of its CUB module is clearly needed. In the future, studies on the structural basis of TSG-6ligand interactions, coupled with exploration of new in vivo and in vitro models, should further our understanding of this exciting and important protein.
![]() |
Note added in proof |
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![]() |
Acknowledgments |
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References |
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