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Secretion of oncostatin M by neutrophils in rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 5, May 2004, pp 1430–1436
DOI 10.1002/art.20166
© 2004, American College of Rheumatology
Secretion of Oncostatin M by Neutrophils in
Rheumatoid Arthritis
Andrew Cross,1 Steven W. Edwards,1 Roger C. Bucknall,2 and Robert J. Moots1
Objective. Neutrophils are known to express and
release a large number of proinflammatory cytokines
when they are stimulated by inflammatory stimuli. The
objective of this study was to determine whether neutrophils express oncostatin M (OSM), a member of the
interleukin-6 family of cytokines that has been implicated in the pathogenesis of inflammatory joint disease.
Methods. Neutrophils were isolated from the
blood of healthy volunteer donors and from the blood
and synovial fluid of patients with rheumatoid arthritis
(RA). OSM levels were measured in cell extracts and in
culture supernatants by Western blotting. Total RNA
was isolated from control and granulocyte–macrophage
colony-stimulating factor (GM-CSF)–treated neutrophils, and OSM messenger RNA levels were quantified
by hybridization of a radiolabeled probe.
Results. GM-CSF stimulated a rapid and transient expression and release of OSM from blood neutrophils, which was more rapid than the expression and
release from blood monocytes. A 28-kd protein was
identified in cell extracts, but an additional 25-kd
isoform was detected in culture supernatants. Synovial
fluid neutrophils could not be stimulated to express
OSM, but this cytokine was detected in cell-free supernatants at various levels.
Conclusion. Blood neutrophils can be stimulated
to express and rapidly release large quantities of OSM.
We propose that this important cytokine is released
from neutrophils as they infiltrate rheumatoid joints
and, thus, contribute to the complex cytokine network
that characterizes RA.
Rheumatoid arthritis (RA) is a severe, chronic
inflammatory condition characterized by a profound
inflammatory immune response that leads to joint damage and destruction, as well as extraarticular disease with
a significant impact on both morbidity and mortality
(1,2). The pathologic processes underlying RA have not
been fully elucidated. However, it is clear that there is a
dysregulation of both the cellular immune system and
the cytokine network (3–5). The success of anti–
proinflammatory cytokine therapy directed at tumor
necrosis factor ␣ (TNF␣) and, to a lesser extent,
interleukin-1␤ (IL-1␤), has highlighted the importance
of these cytokines in rheumatoid disease processes (6–
10). However, such therapies are not beneficial to all
patients, which suggests that other processes are also
important. Similarly, the most-studied cellular component of the immune response in RA is the T cell.
However, development of a truly effective anti–T cell
therapy has remained elusive, which suggests that other
cellular components of the immune system play important pathologic roles in RA.
Polymorphonuclear neutrophils are circulating
phagocytes that participate in immune and inflammatory responses to both endogenous and exogenous stimuli. These cells are the most abundant of the immune
system and represent the greatest proportion of cells
that infiltrate the rheumatoid joint (11). However, they
have been subjected to a disproportionately low number
of investigations in RA. These cells are clearly present in
vast numbers in synovial effusions in patients with RA
(12,13). They are also focused in synovial tissue at sites
of erosions and are capable of inducing profound inflammatory responses and damage (14,15). We and
other investigators have shown that neutrophils are not
merely short-lived, terminally differentiated cells, but
rather, they are able to live for long periods of time
Supported by Aintree Arthritis Trust UK and Wyeth Pharmaceuticals UK.
1
Andrew Cross, PhD, Steven W. Edwards, PhD, Robert J.
Moots, MD, PhD: University of Liverpool, Liverpool, UK; 2Roger C.
Bucknall, MD: Royal Liverpool University Hospital, Liverpool, UK.
Address correspondence and reprint requests to Robert J.
Moots, MD, PhD, University of Liverpool, Academic Rheumatology
Unit, University Hospital Aintree, Longmoor Lane, Liverpool L9
7AL, UK. E-mail: rjmoots@liv.ac.uk.
Submitted for publication June 13, 2003; accepted in revised
form January 10, 2004.
1430
SECRETION OF OSM BY NEUTROPHILS IN RA
under conditions of inflammation and can up-regulate a
variety of receptors, including class II major histocompatibility complex molecules, and a range of cytokines
(16–18). A clear role for neutrophils in both the initiation and development of experimental arthritis in mice
has recently been demonstrated (19).
Oncostatin M (OSM) is a pleiotropic cytokine of
the IL-6 family (20), but its role in inflammation is
currently ambiguous. For example, OSM has been
shown to have antiinflammatory effects by regulating
tissue inhibitor of metalloproteinases 1 and antiproteases, inhibiting IL-1–induced IL-8 production by lung
fibroblasts (21–24), and stimulating hepatocytes to secrete acute-phase proteins (25). Furthermore, anti-OSM
antibodies have been shown to ameliorate experimental
arthritis in mice (26). Conversely, OSM has been shown
to exert proinflammatory effects in other situations. For
example, it induces adhesion and chemotaxis in neutrophils and induces chemokine production by endothelial
cells and synovial fibroblasts (27,28). Enhanced expression of OSM induces inflammation and arthritis in mice,
and it is found in elevated concentrations in rheumatoid
synovial fluid. Oncostatin synergizes with IL-1 to promote cartilage degradation, and it induces granulocyte
colony-stimulating factor and granulocyte–macrophage
colony-stimulating factor (GM-CSF) production by endothelial cells (29). Clearly, all of these properties may
be of potential relevance in RA.
In this study, we observed enhanced production
of OSM in neutrophils stimulated by GM-CSF. We
describe the dynamics of OSM production and secretion
by neutrophils from the peripheral blood of healthy
volunteer donors and in matched peripheral blood and
synovial fluid samples from patients with RA.
MATERIALS AND METHODS
Materials. Neutrophil isolation medium was obtained
from Cardinal Associates (Santa Fe, NM), Ficoll-Paque from
Amersham Pharmacia (Uppsala, Sweden), RPMI 1640 medium from Gibco BRL (Paisley, UK), and fetal calf serum
from Sigma (Poole, UK). The cytokines used were GM-CSF
(Glaxo, Greenford, UK) and TNF␣ (Calbiochem, Nottingham,
UK). Anti-OSM antibody (catalog no. RDI-ONCSabrP) and
recombinant OSM (catalog no. RDI-310) were purchased
from Research Diagnostics (Flanders, NJ); anti-OSM antibody
obtained from Abcam (catalog no. ab9633; Abcam, Cambridge, UK) was used to confirm the results. A BD Atlas Nylon
Array (catalog no. 7744-1, human cytokine/receptor) was used
for gene expression analysis and was purchased from BD
Clontech (Basingstoke, UK)
Cell isolation and culture. This study was approved by
the Institutional Review Board of the South Sefton Research
1431
Ethics Committee. Peripheral blood cells were prepared from
heparinized venous blood obtained from healthy donors, and
patients with RA (fulfilling the American College of Rheumatology [formerly, the American Rheumatism Association] 1987
revised criteria [30]), and patients with other inflammatory joint
arthropathies. Cells were separated into neutrophil and mononuclear cell fractions by using neutrophil isolation medium (as
described in the manufacturer’s instructions) (31). Contaminating
erythrocytes were removed by hypotonic lysis. Neutrophils from
the synovial fluid of RA patients were isolated soon after aspiration, by use of Ficoll-Paque in a 1-step centrifugation method
(32). Neutrophils were routinely examined for purity and viability
using trypan blue exclusion (⬎97% and ⬎98%, respectively)
immediately after isolation. Purity was confirmed using morphologic analysis of cytospin preparations and CD15 and/or CD16
expression.
Purified neutrophils were resuspended in 1640 RPMI,
supplemented with 10% fetal calf serum at 5 ⫻ 106 cells/ml,
and cultured at 37°C in a humidified chamber containing 5%
CO2. Cytokines were added as indicated. U937 cells were
cultured and maintained in RPMI 1640 medium supplemented
with 10% fetal calf serum and 1 mM L-glutamine. Cells were
stimulated with phorbol myristate acetate (80 ng/ml), and both
the supernatant and cells were collected and processed as
described below.
RNA isolation and analysis. Total RNA was extracted
from 3 ⫻ 107 isolated control and GM-CSF–treated (45
minutes) peripheral blood neutrophils using TRIzol reagent
(Gibco BRL), as described in the manufacturer’s instructions.
RNA was then further purified using an RNeasy mini kit
(Qiagen, Crawley, UK). Probe preparation utilized a polymerase chain reaction complementary DNA (cDNA) synthesis kit
(BD Clontech), which was then labeled with 32P-dATP (50
␮Ci) for 30 minutes at 50°C. Labeled cDNA was purified from
unincorporated 32P-labeled nucleotides and small (⬍0.1-kb)
cDNA fragments using spin-column chromatography.
Hybridization of cDNA probes. The cDNA prepared
above were then hybridized to BD Atlas Nylon Array filter arrays,
exactly as described in the manufacturer’s instructions. Briefly, 2
identical Atlas array membranes were prehybridized with prewarmed hybridization solution (ExpressHyb; BD Clontech) containing denatured salmon testes DNA (0.1 mg/ml) for 30 minutes
at 68°C. Labeled probe was denatured using a denaturing solution
and, after neutralization, was added to the prehybridized membrane. Hybridization was performed overnight at 68°C, with
continuous agitation for 18 hours. The membranes were then
washed consecutively in prewarmed wash solution 1 (2⫻ saline–
sodium citrate [SSC] and sodium dodecyl sulfate [SDS; 1%
weight/volume]) and wash solution 2 (0.1⫻ SSC and SDS [0.5%
w/v]) for 30 minutes each at 68°C, with continuous agitation. The
membranes were then removed from the hybridization containers, blotted dry, sealed in plastic wrap, and analyzed.
A Storm 840 PhosphorImager (Molecular Dynamics,
Chesham, UK) was used for membrane analysis. Captured
images were analyzed and hybridization signals quantified
using ImageQuant version 5.2 software (Molecular Dynamics).
Background signals were subtracted from each membrane, and
signals were normalized, using levels of housekeeping genes as
standards. Results were interpreted with the AtlasInfo database (BD Clontech).
1432
CROSS ET AL
Statistical analysis. Data sets were analyzed using
Student’s t-test.
Figure 1. Oncostatin M (OSM) expression by healthy control blood
neutrophils in response to granulocyte–macrophage colonystimulating factor (GM-CSF). A and B, Results of 1 of 3 experiments
in which mRNA from control and GM-CSF–treated neutrophils (50
units/ml for 45 minutes) was hybridized to an Atlas macroarray filter.
Only that portion of the filter with the OSM target (spotted in
duplicate) is shown. The hybridization signal in B was 150–200 times
greater than that in A, based on quantitation by PhosphorImager
analysis. C, Healthy control blood neutrophils incubated for 2 hours at
37°C in the absence (0) and presence of 50 units/ml of GM-CSF. At the
indicated times, samples were obtained and centrifuged, and OSM
levels in the cell pellets and culture supernatants were detected by
Western blotting. A Western blot of actin in cell pellets was performed
to confirm equality of loading (bottom).
Western analysis. In experiments in which both the
supernatant and pellet were analyzed, cells were cultured at
2 ⫻ 107/ml. At each time point, 200 ␮l was removed and
centrifuged and 150 ␮l of supernatant was removed and added
to 30 ␮l of boiling 5⫻ sample buffer with phenylmethylsulfonyl
fluoride (PMSF; 1 mM). Cell pellets were then washed in
phosphate buffered saline, centrifuged, and then lysed with 150
␮l of ice-cold lysis buffer (20 mM Tris, pH 7.5, 1 mM EDTA,
150 mM NaCl containing 1% v/v Igepal, 10 mM NaF, 10 ␮g/ml
of aprotinin, 10 ␮g/ml of leupeptin, and 10 ␮g/ml of pepstatin
A) before the addition of boiling 5⫻ sample buffer and 1 mM
PMSF. All samples were stored at ⫺80°C until analyzed.
SDS–polyacrylamide gel electrophoresis (using 12%
gels) was used to separate protein extracts, and OSM detection
was performed using the primary antibody and an enhanced
chemiluminescence detection system. Densitometry on carefully exposed blots (to avoid film saturation) was performed
with Image 1.44 VDM software (National Institutes of Health,
Bethesda, MD; online at: http://rsb.info.nih.gov/nih-image/).
Ponceau S–stained actin on membranes confirmed equivalence
of loading.
RESULTS
OSM expression by peripheral blood neutrophils
from healthy control subjects. Neutrophils isolated from
the blood of healthy volunteers expressed negligible
levels of messenger RNA (mRNA) for OSM, as detected by hybridization to a DNA filter array (Figure
1A). However, in the same preparation of neutrophils
treated for 45 minutes with GM-CSF, far higher levels of
mRNA for OSM were detected (Figure 1B). Quantitation of hybridization signals obtained from control and
GM-CSF–treated neutrophils indicated a 150–200-fold
increase in counts following GM-CSF treatment.
Neutrophils isolated from the blood of healthy
controls exhibited low, but detectable, levels of OSM
protein, as measured by Western blotting (Figure 1C).
Cellular levels of this protein increased rapidly after
GM-CSF treatment, peaking at 90–120 minutes after
stimulation and declining thereafter (Figure 2). Thus, by
5 hours after stimulation with GM-CSF, cellular levels of
OSM were approaching control, unstimulated levels.
Control blood neutrophils secreted extremely low
levels of OSM that were below the level of detection of
the assay. However, following GM-CSF treatment, OSM
was detectable in neutrophil supernatants and reached
maximal levels between 90 and 120 minutes after stim-
Figure 2. Kinetics of OSM expression and secretion by healthy control
blood neutrophils in response to GM-CSF. Neutrophils from the blood
of healthy controls were incubated as described in Figure 1. At the
indicated times after addition of GM-CSF, OSM levels in cell pellets
(solid bars) and culture supernatants (open bars) were determined by
Western blotting. Values are the mean and SD (n ⫽ 3 samples).
Relative levels of OSM are expressed as the percentage of a positive
control (phorbol myristate acetate–treated U937 cells). See Figure 1
for definitions.
SECRETION OF OSM BY NEUTROPHILS IN RA
Figure 3. Kinetics of OSM expression and secretion by healthy control
peripheral blood mononuclear cells (PBMCs) in response to GM-CSF.
PBMCs from healthy controls were incubated as described in Figure 1.
At the indicated times after addition of GM-CSF, OSM levels in cell
pellets (solid bars) and culture supernatants (open bars) were determined by Western blotting. Values are the mean and SD (n ⫽ 3
samples). Relative levels of OSM are expressed as the percentage of a
positive control (phorbol myristate acetate–treated U937 cells). See
Figure 1 for other definitions.
ulation (Figures 1C and 2). After this time, secreted
levels also declined. Thus, GM-CSF treatment resulted
in a rapid activation of both the expression and the
secretion of OSM from neutrophils. Both expression and
secretion were transient, falling to baseline (unstimulated) levels by ⬃6–8 hours. It is curious to note, that
while only a single band of OSM was detected intracellularly (at 28 kd), 2 proteins were detected in culture
supernatants, at 28 kd and 25 kd.
We then tested whether another proinflammatory
cytokine, TNF␣, was also capable of stimulating OSM
expression and secretion. TNF␣ was shown to stimulate
increased OSM expression by neutrophils, but very little
secretion of this cytokine was detected (data not shown).
OSM expression by peripheral blood mononuclear cells (PBMCs) from healthy controls. GM-CSF
could also stimulate OSM expression in PBMCs, but
peak expression was detected by 2–3 hours after stimulation (Figure 3), compared with the very rapid expression (60–90 minutes) observed following stimulation of
neutrophils. Similarly, secretion of OSM was observed
after GM-CSF treatment, but again, this was slower than
that observed after stimulation of neutrophils, with
maximal levels detected extracellularly by 4–5 hours
after stimulation. Similarly, TNF␣ could stimulate OSM
1433
expression by mononuclear cells, but again, very little
secretion was observed (data not shown).
Thus, GM-CSF stimulated OSM expression and
secretion from both neutrophils and mononuclear cells,
but the kinetics of activation and secretion were much
faster for neutrophils.
OSM expression by neutrophils from healthy
controls and patients with RA. Cellular levels of OSM
were not significantly different in neutrophils isolated
from healthy controls compared with those from patients with RA, as analyzed immediately after purification (Figure 4). Similarly, neutrophils from the blood of
patients with RA could be stimulated by GM-CSF to
express and secrete OSM, and the levels observed
following simulation were not significantly different
from those obtained with healthy control neutrophils
(data not shown). In the absence of GM-CSF, cellular
levels of OSM remained fairly constant during culture of
blood neutrophils from controls or patients (Figure 5).
However, cellular levels of OSM were rapidly enhanced
by GM-CSF treatment.
Figure 4. Oncostatin M (OSM) expression by neutrophils isolated
from the blood of healthy controls and patients with rheumatoid
arthritis (RA). Neutrophils were isolated from the blood of healthy
controls and patients with RA, and cellular OSM levels were measured
by Western blotting immediately after isolation. Neutrophils were also
incubated at 37°C for 1 hour with 50 units/ml of granulocyte–
macrophage colony-stimulating factor (GM-CSF) prior to measurement of OSM levels and densitometry. Values are the mean and SD
(n ⫽ 6 GM-CSF–treated samples, n ⫽ 6 control samples, and n ⫽ 9
RA samples). Similar effects of GM-CSF on RA blood neutrophils
were observed.
1434
Figure 5. OSM expression by blood neutrophils from patients with
RA. Neutrophils were isolated from the blood of patients with RA and
then incubated in the absence or presence of GM-CSF for up to 3
hours at 37°C. At the indicated times, samples were removed for
measurement of cellular OSM levels by Western blotting. Values are
the mean and SD (n ⫽ 3 samples). Levels of OSM in healthy controls,
as measured by densitometry, were designated as 100%. See Figure 4
for definitions.
Neutrophils isolated from the synovial fluid of
patients with RA were shown to express OSM. Immediately after isolation, cellular levels were slightly decreased compared with levels in paired blood neutrophils, but this did not reach statistical significance (P ⫽
0.07; n ⫽ 8). However, GM-CSF could not enhance the
expression of this cytokine (Figure 6). Indeed, in the
absence of GM-CSF (and in contrast to blood neutrophils), expression of OSM rapidly declined and was
virtually undetectable by 3 hours of culture ex vivo
(Figures 6 and 7). In contrast, GM-CSF slightly delayed
the rate at which OSM levels per cell decreased, but no
clear up-regulation of OSM was seen after GM-CSF
treatment, as was observed in blood cells from controls
or patients.
OSM levels in RA synovial fluid. Cell-free synovial fluid samples derived from patients with RA were
Figure 6. OSM expression by synovial fluid neutrophils from patients
with RA. Neutrophils were isolated from the synovial fluid of patients
with RA and then incubated in the absence or presence of GM-CSF
for up to 3 hours at 37°C. At the indicated times, samples were
removed for measurement of cellular OSM levels by Western blotting.
See Figure 4 for definitions.
CROSS ET AL
Figure 7. OSM expression by synovial fluid neutrophils from patients
with RA. Neutrophils were isolated from the synovial fluid of patients
with RA and then incubated in the absence or presence of GM-CSF
for up to 3 hours at 37°C. At the indicated times, samples were
removed for measurement of cellular OSM levels by Western blotting.
Values are the mean and SD (n ⫽ 3 samples). Levels of OSM in
healthy controls, as measured by densitometry, were designated as
100%. See Figure 4 for definitions.
tested for levels of OSM by Western blotting, using a
protein extract from U937 cells as a positive control.
OSM was detectable in almost all samples examined, but
there was wide variation in the levels. Furthermore, the
relative levels of the 2 isoforms of extracellular OSM (at
25 kd and 28 kd) varied widely. For example, some
samples contained approximately equal levels of both
isoforms (e.g., sample 6), while others contained primarily the 28-kd isoform (e.g., sample 11) or primarily the
25-kd isoform (e.g., sample 42) (Figure 8).
The relative levels of OSM detected in a range of
Figure 8. Relative oncostatin M (OSM) levels in synovial fluid from
patients with rheumatoid arthritis (RA). Cell-free synovial fluid was
isolated from different patients with RA (indicated by the numbers
across the top), and 10 ␮l of each sample (diluted in 200 ␮l of sample
buffer) was analyzed by Western blotting to determine relative OSM
levels. Positive represents a cell extract obtained after phorbol myristate acetate treatment of U937 cells.
SECRETION OF OSM BY NEUTROPHILS IN RA
Figure 9. Relative oncostatin M (OSM) levels in synovial fluid from
patients with rheumatoid arthritis (RA). Cell-free synovial fluid was
isolated from different patients with RA (indicated by the numbers
across the bottom), and 10 ␮l of each sample (diluted in 200 ␮l of
sample buffer) was analyzed by Western blotting to determine relative
OSM levels. Data are shown after quantitation by densitometry.
Positive represents a cell extract obtained after phorbol myristate
acetate treatment of U937 cells.
rheumatoid synovial fluid samples are shown in Figure 9.
In some of the samples, OSM levels were just above the
level of detection, whereas in others, OSM levels exceeded those in the positive control.
DISCUSSION
Human neutrophils secrete a wide range of cytokines, and these secreted molecules have the capacity to
direct the progress of an inflammatory reaction by
influencing the activity of immune cells and tissues. In
common with other cytokines known to be expressed by
neutrophils, oncostatin M is not secreted in significant
amounts by resting blood neutrophils, but its expression
and secretion are rapidly activated by proinflammatory
signals such as GM-CSF, which is known to be secreted
by synovial cells in RA (33). This activation of expression
is extremely rapid, with maximal cellular levels occurring
within 1–2 hours of stimulation and maximal secreted
levels occurring by 2 hours of stimulation. This contrasts
with the rather slower kinetics of expression and secretion observed following addition of GM-CSF to PBMCs.
Neutrophils have typically been reported to activate
cytokine expression more rapidly than do mononuclear
cells (17). As with other cytokines, we show that on a cell
basis, neutrophils secrete ⬃20% of the levels of OSM as
mononuclear phagocytes. However, since neutrophil
numbers during inflammation can be far higher than
mononuclear cell numbers, neutrophil-derived OSM
expression is likely to be of extreme importance in
disease pathogenesis.
1435
Neutrophils have previously been reported to express OSM, but, to our knowledge, there are no reports of
2 isoforms of this cytokine in the literature. While we
detected only a 28-kd form in cell extracts (the reported
molecular mass of the cytokine [34]), we consistently
detected an additional form at 25 kd in neutrophil supernatants. These isoforms were detected when the Western
blots were developed using 2 separate anti-OSM antibodies. Curiously, we also detected both isoforms in the
synovial fluid of patients with RA, but there was great
variation between donors in both the levels of OSM in
different fluids and the relative levels of the 2 isoforms
detected. For example, in some samples, both isoforms
were detected in approximately equal amounts, while in
others, either the 28-kd or the 25-kd isoform predominated. The molecular identity of the 25-kd isoform is
unknown, but it may represent a processed form of the
cytokine, perhaps as a result of partial proteolytic cleavage.
It would also be extremely interesting to determine
whether the 2 isoforms have different stabilities or different
biologic functions. It will then be possible to determine
whether these 2 molecules play different roles in RA, and
hence, the biologic significance of the variation in the
presence of these 2 molecules in different synovial fluid
samples could be assessed.
Somewhat to our surprise, we could not detect
significantly elevated levels of OSM in neutrophils isolated
from the blood of RA patients. Indeed, neutrophils isolated from the blood of these patients behaved in a manner
similar to that of healthy control neutrophils in terms of
their responsiveness to GM-CSF. Synovial fluid neutrophils behaved quite differently, however. OSM was clearly
detected in freshly isolated synovial fluid neutrophils, but in
contrast to blood cells, the levels of this cytokine rapidly
declined as they were cultured in vitro in the absence of
GM-CSF. Thus, after 3 hours of incubation in culture,
cellular levels of this cytokine in synovial fluid neutrophils
were virtually undetectable. Furthermore, the addition of
GM-CSF did not stimulate OSM expression in these
synovial fluid neutrophils, but rather, partially slowed the
rate of disappearance of this cytokine.
From these observations we conclude that the
synovial fluid neutrophils have already been triggered to
express and secrete OSM within the joints, and so, are
desensitized to further stimulation. Indeed, this scenario
may explain the presence of OSM within these joint fluids,
although it must be stressed that cells other than neutrophils that are present within diseased joints can also
contribute to the presence of this cytokine. Thus, based
upon the observations in this study, we conclude that
neutrophils are triggered to secrete OSM very soon after
1436
CROSS ET AL
entering the diseased joint, possibly when in transit through
the pannus, where they will encounter GM-CSF in significant amounts, and that the release of OSM contributes to
the pathologic disease processes. As the role of OSM in
disease pathogenesis remains enigmatic, it is uncertain as
yet if this neutrophil-dependent cytokine release is harmful
or beneficial to the disease process.
REFERENCES
1. Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis.
J Rheumatol 1999;26:717–9.
2. Grossman JM, Brahn E. Rheumatoid arthritis: current clinical and
research directions. J Womens Health 1997;6:627–38.
3. Beaulieu AD, McColl SR. Differential expression of two major
cytokines produced by neutrophils, interleukin-8 and the interleukin-1 receptor antagonist, in neutrophils isolated from the synovial
fluid and peripheral blood of patients with rheumatoid arthritis.
Arthritis Rheum 1994;37:855–9.
4. Farahat MN, Yanni G, Poston R, Panayi GS. Cytokine expression
in synovial membranes of patients with rheumatoid arthritis and
osteoarthritis. Ann Rheum Dis 1993;52:870–5.
5. Ridderstad A, Abedi-Valugerdi M, Moller E. Cytokines in rheumatoid arthritis. Ann Med 1991;23:219–23.
6. Abramson SB, Amin A. Blocking the effects of IL-1 in rheumatoid
arthritis protects bone and cartilage. Rheumatology (Oxford)
2002;41:972–80.
7. Catrina AI, Lampa J, Ernestam S, af Klint E, Bratt J, Klareskog L,
et al. Anti-tumour necrosis factor (TNF)-␣ therapy (etanercept)
down-regulates serum matrix metalloproteinase (MMP)-3 and
MMP-1 in rheumatoid arthritis. Rheumatology (Oxford) 2002;41:
484–9.
8. Feige U, Hu YL, Gasser J, Campagnuolo G, Munyakazi L, Bolon
B. Anti-interleukin-1 and anti-tumor necrosis factor-␣ synergistically inhibit adjuvant arthritis in Lewis rats. Cell Mol Life Sci
2000;57:1457–70.
9. Geborek P, Crnkic M, Petersson IF, Saxne T. Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical
experience using a structured follow up programme in southern
Sweden. Ann Rheum Dis 2002;61:793–8.
10. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid
arthritis. Annu Rev Med 2000;51:207–29.
11. Edwards SW, Hallett MB. Seeing the wood for the trees: the
forgotten role of neutrophils in rheumatoid arthritis. Immunol
Today 1997;18:320–4.
12. Chatham WW, Swaim R, Frohsin H Jr, Heck LW, Miller EJ,
Blackburn WD Jr. Degradation of human articular cartilage by
neutrophils in synovial fluid. Arthritis Rheum 1993;36:51–8.
13. Kitsis E, Weissmann G. The role of the neutrophil in rheumatoid
arthritis. Clin Orthop 1991;265:63–72.
14. Kowanko IC, Ferrante A, Clemente G, Youssef PP, Smith M.
Tumor necrosis factor priming of peripheral blood neutrophils
from rheumatoid arthritis patients. J Clin Immunol 1996;16:
216–21.
15. Mohr W, Pelster B, Wessinghage D. Polymorphonuclear granulocytes in rheumatic tissue destruction. VI. The occurrence of PMNs
in menisci of patients with rheumatoid arthritis. Rheumatol Int
1984;5:39–44.
16. Cassatella MA, Gasperini S, Russo MP. Cytokine expression and
release by neutrophils. Ann N Y Acad Sci 1997;832:233–42.
17. Quayle JA, Adams S, Bucknall RC, Edwards SW. Interleukin-1
expression by neutrophils in rheumatoid arthritis. Ann Rheum Dis
1995;54:930–3.
18. Cross A, Bucknall RC, Castella MA, Edwards SW, Moots RJ.
Synovial fluid neutrophils transcribe and express class II major
histocompatibility complex molecules in rheumatoid arthritis. Arthritis Rheum 2003;48:2796–806.
19. Wipke BT, Allen PM. Essential role of neutrophils in the initiation
and progression of a murine model of rheumatoid arthritis.
J Immunol 2001;167:1601–8.
20. Lahiri T, Laporte JD, Moore PE, Panettieri RA Jr, Shore SA.
Interleukin-6 family cytokines: signaling and effects in human
airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol
2001;280:L1225–32.
21. Langdon C, Leith J, Smith F, Richards CD. Oncostatin M
stimulates monocyte chemoattractant protein-1– and interleukin1–induced matrix metalloproteinase-1 production by human synovial fibroblasts in vitro. Arthritis Rheum 1997;40:2139–46.
22. Richards CD, Kerr C, Tanaka M, Hara T, Miyajima A, Pennica D,
et al. Regulation of tissue inhibitor of metalloproteinase-1 in
fibroblasts and acute phase proteins in hepatocytes in vitro by
mouse oncostatin M, cardiotrophin-1, and IL-6. J Immunol 1997;
159:2431–7.
23. Wahl AF, Wallace PM. Oncostatin M in the anti-inflammatory
response. Ann Rheum Dis 2001;60:75–80.
24. Wallace PM, MacMaster JF, Rouleau KA, Brown TJ, Loy JK,
Donaldson KL, et al. Regulation of inflammatory responses by
oncostatin M. J Immunol 1999;162:5547–55.
25. Richards CD, Shoyab M, Brown TJ, Gauldie J. Selective regulation of metalloproteinase inhibitor (TIMP-1) by oncostatin M in
fibroblasts in culture. J Immunol 1993;150:5596–603.
26. Plater-Zyberk C, Buckton J, Thompson S, Spaull J, Zanders E,
Papworth J, et al. Amelioration of arthritis in two murine models
using antibodies to oncostatin M. Arthritis Rheum 2001;44:
2697–702.
27. Kerfoot SM, Raharjo E, Ho M, Kaur J, Serirom S, McCafferty
DM, et al. Exclusive neutrophil recruitment with oncostatin M in
a human system. Am J Pathol 2001;159:1531–9.
28. Modur V, Feldhaus MJ, Weyrich AS, Jicha DL, Prescott SM,
Zimmerman GA, et al. Oncostatin M is a proinflammatory
mediator: in vivo effects correlate with endothelial cell expression
of inflammatory cytokines and adhesion molecules. J Clin Invest
1997;100:158–68.
29. Catterall JB, Carrere S, Koshy PJ, Degnan BA, Shingleton WD,
Brinckerhoff CE, et al. Synergistic induction of matrix metalloproteinase 1 by interleukin-1␣ and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and
activator protein 1 transcription factors via a novel mechanism.
Arthritis Rheum 2001;44:2296–310.
30. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association 1987
revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum 1988;31:315–24.
31. Fossati G, Moulding DA, Spiller DG, Moots RJ, White MR,
Edwards SW. The mitochondrial network of human neutrophils:
role in chemotaxis, phagocytosis, respiratory burst activation and
commitment to apoptosis. J Immunol 2003;170:1964–72.
32. Edwards SW, Hughes V, Barlow J, Bucknall R. Immunological
detection of myeloperoxidase in synovial fluid from patients with
rheumatoid arthritis. Biochem J 1988;250:81–5.
33. Alvaro-Gracia JM, Zvaifler NJ, Brown CB, Kaushansky K, Firestein GS. Cytokines in chronic inflammatory arthritis. VI. Analysis
of the synovial cells involved in granulocyte-macrophage colonystimulating factor production and gene expression in rheumatoid
arthritis and its regulation by IL-1 and tumor necrosis factor-␣.
J Immunol 1991;146:3365–71.
34. Bruce AG, Hoggatt IH, Rose TM. Oncostatin M is a differentiation factor for myeloid leukemia cells. J Immunol 1992;149:
1271–5.
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