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on Macrophage Inflammatory Protein-3 Production in Rheumatoid Arthritis: Regulation by Soluble Receptors and Th2 Cytokines1
Departments of Immunology and Rheumatology and Institut National de la Santé et de la Recherche Médicale, Unité 403, Hôpital Edouard Herriot, Lyon, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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is a chemokine involved
in the migration of T cells and immature dendritic cells. To study the
contribution of proinflammatory cytokines and chemokines to the
recruitment of these cells in rheumatoid arthritis (RA) synovium, we
looked at the effects of the monocyte-derived cytokines IL-1
and
TNF- and the T cell-derived cytokine IL-17 on MIP-3 production by
RA synoviocytes. Addition of IL-1, IL-17, and TNF- induced
MIP-3 production in a dose-dependent manner. At optimal
concentrations, IL-1 (100 pg/ml) was much more potent than IL-17
(100 ng/ml) and TNF- (100 ng/ml). When combined at lower
concentrations, a synergistic effect was observed. Conversely, the
anti-inflammatory cytokines IL-4 and IL-13 inhibited MIP-3
production by activated synoviocytes, but IL-10 had no effect. Synovium
explants produced higher levels of MIP-3 in RA than osteoarthritis
synovium. MIP-3-producing cells were located in the lining layer and
perivascular infiltrates in close association with CD1a immature
dendritic cells. Addition of exogenous IL-17 or IL-1 to synovium
explants increased MIP-3 production. Conversely, specific soluble
receptors for IL-1, IL-17, and TNF- inhibited MIP-3
production to various degrees, but 95% inhibition was obtained only
when the three receptors were combined. Similar optimal inhibition was
also obtained with IL-4, but IL-13 and IL-10 were less active. These
findings indicate that interactions between monocyte and Th1
cell-derived cytokines contribute to the recruitment of T cells and
dendritic cells by enhancing the production of MIP-3 by
synoviocytes. The inhibitory effect observed with cytokine-specific
inhibitors and Th2 cytokines may have therapeutic
applications. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and MIP-1; and monocyte chemoattractant protein-1
and RANTES, which recruit T cells and monocytes
(2, 3, 4, 5, 6, 7, 8).
MIP-3, also called liver and activation-regulated chemokine
(9), Exodus-1, or CCL20, is a CC chemokine with an in vivo
distribution rather restricted to mucosal and inflamed tissues
(10, 11, 12, 13). Furthermore, MIP-3 is inducible in vitro by
mediators of inflammation and is expressed by both hemopoietic
(dendritic cells (DC), monocytes, granulocytes, and T and B
lymphocytes) and nonhemopoietic cells (endothelial cells, tumor cells)
(12, 14, 15, 16). MIP-3 was found to be the most powerful
chemokine in inducing the migration of
CD34+-derived immature DC compared with
MIP-1 and RANTES (10, 12, 17, 18, 19, 20). Because of the link
between MIP-3 expression and inflammation, we considered the
contribution of MIP-3 to RA pathogenesis. Indeed, the synovitis has
been previously described as a lymphoid organ located in an ectopic
position. These features suggest a role for chemotactic factors in the
migration of lymphocytes and DC leading to the local organization that
is characteristic of the follicular structure of RA synovium.
To address this issue we analyzed the expression and cellular source of
MIP-3 in RA synoviocytes and synovium tissue. The data indicate that
MIP-3 production by RA synovium and synoviocytes is stimulated by
proinflammatory cytokines and can be regulated by their specific
inhibitors and Th2 cytokines.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Murine IL-17R (21), dimeric human TNF receptor
p80/IgG1:Fc fusion protein (22), and human soluble type II
IL-1R (23) were provided by Dr. K. Mohler (Immunex,
Seattle, WA), and human rIL-4, rIL-10, rIL-13, and rIL-17 were provided
by Dr. F. Fossiez (Schering-Plough Research Center, Dardilly, France).
Human rIL-1 and human rTNF- were purchased from Sigma-Aldrich
(St. Louis, MO).
Synovium explant and synoviocyte cultures
Rheumatoid synovium samples were obtained from 39 patients with
RA, according to the revised criteria of the American College of
Rheumatology (24), who were undergoing knee or
wrist synovectomy or joint replacement. Osteoarthritis (OA) synovium
samples were obtained during joint replacement from 29 patients.
Synovium explant cultures were performed as previously described
(25). Briefly, fat and fibrous tissues were removed, and
synovium was cut into small explants with a volume of approximately 5
mm3. Explants of synovium were cultured in
triplicate in complete medium consisting of MEM medium (Life
Technologies, Grand Island, NY) with 2 mM L-glutamine, 100
U/ml penicillin, 50 mg/ml gentamicin, 20 mM HEPES buffer, and 10% FCS.
Cultures were performed at 37°C in a 5%
CO2/95% air-humidified environment.
To isolate synoviocytes, synovium explants were finely minced and digested with 4 mg/ml collagenase (Worthington, Freehold, NJ) in Dulbecco’s PBS (Life Technologies) for 2–3 h at 37°C (26). After centrifugation, cells were suspended in complete medium and cultured in 100-mm culture petri dishes. After 48 h, nonadherent cells were removed. Adherent cells were cultured in complete medium and at confluence were trypsinized and passaged in 150-cm2 culture flasks. Synoviocytes were used between passages three and eight. At this time they were a homogenous population of fibroblast-like cells, negative for the expression of CD1, CD3, CD19, CD14, and HLA-DR and positive for the expression of CD10, CD44, and CD54 as determined by FACS analysis.
To obtain culture supernatants, synoviocytes were plated in 96-well plates at 104 cells/well in 200 µl of complete medium. The cytokines to be tested were added at the onset of culture. Supernatants were collected after 72 h of culture.
Measurement of MIP-3 levels
MIP-3 levels were measured by a two-site sandwich ELISA.
Briefly, supernatants or serial dilutions of MIP-3 standards were
incubated for 2 h and 30 min at 37°C in 96-microtiter plates
(Nunc, Roskilde, Denmark) and coated overnight at 4°C with the mouse
319F6 anti-MIP-3 mAb (1 µg/ml). These two mAb were provided by
Dr. C. Caux (Schering-Plough). After washing, a peroxidase-coupled
mouse anti-MIP-3 mAb (1 µg/ml) was added and incubated for
2 h and 30 min at 37°C. After revelation with
tetramethylbenzidine (Sigma-Aldrich), the plates were read at
450 nm.
MIP-3 mRNA expression
RNA was extracted from synovium biopsies by the guanidinium
isocyanate method (27). To synthesize cDNA, 1 µg of
total RNA was incubated with 2 µg oligo(dT) primer (Boehringer
Mannheim, Meylan, France), 0.5 mM dNTP, 10 mM DTT, 10 µl of 10x RT
buffer, and 20 U of reverse transcriptase (Boehringer Mannheim). The
PCR reaction was performed using 5 µl of this cDNA in the presence of
50 mM KCl, 10 mM Tris (pH 8.3), 1.5 mM MgCl2, 200
µM dNTPs, 0.5 µM of each primer, and 2.5 U of Taq
polymerase (Boehringer Mannheim) in a total of 50 µl and was
incubated at 94°C for 3 min, 61°C for 1 min, and 72°C for 2 min.
This cycle was repeated 40 times. PCR products (10 µl) were separated
by electrophoresis in a 1.5% agarose gel and visualized by ethidium
bromide staining. After transfer to a nylon membrane (Boehringer
Mannheim) and prehybridization, membranes were hybridized overnight at
68°C with an MIP-3 oligonucleotide (5'-GAA-TCA-GAA-GCA-AGC-AA-3')
and an actin cDNA probe labeled with digoxigenin. After stringency
washes, membranes were incubated with an Ab conjugated to alkaline
phosphatase and chemiluminescence substrate (Boehringer Mannheim).
Blots were exposed to x-ray film (Kodak, Rochester, NY). Primer
sequences were as follows: MIP-3 sense,
5'-TTG-CTC-CTG-GCT-GCT-TTG-3'; MIP-3 antisense,
5'-ACC-CTC-CAT-GAT-GTG-GAAC-3'; actin sense,
5'-GGG-TCA-GAAGGA-TTC-CTA-TGG-3'; and actin antisense,
5'-CTC-CTT-AAT-GTC- ACG-CAC-GAT-TTC-3'.
Immunohistochemistry
RA synovium samples were fixed in 4% phosphate-buffered
paraformaldehyde and then embedded in paraffin. Four-micrometer
sections were cut and mounted on glass slides. To block nonspecific
activities, sections were pretreated with avidin and biotin solutions
(blocking kit; Vector Laboratories, Burlingame, CA) for 10 min for each
step and with 0.3% hydrogen peroxide (Sigma-Aldrich) for 15 min at
room temperature. After brief washing in PBS, the sections were
incubated with blocking serum (2% normal human serum) for at least 30
min before adding the primary Abs. Sections were stained with an
anti-human MIP-3 goat polyclonal Ab (IgG; R&D Systems,
Minneapolis, MN) for 1 h at room temperature in a humid
atmosphere. Binding of the anti-human MIP-3 Ab was detected with
a biotinylated rabbit anti-goat IgG followed by
streptavidin-peroxidase. Peroxidase staining was revealed using
3-amino-9-ethylcarbazole as substrate. Negative controls were
established by adding nonspecific isotype controls as primary Abs. For
double staining with anti-MIP-3 and anti-CD1a (IgG2b; BD
Biosciences, Pont de Claix, France) Abs, after an initial blocking with
rabbit serum and BSA, primary anti-MIP-3 Ab was followed by a
rabbit biotinylated anti-goat IgG and
streptavidin-peroxidase. Peroxidase was developed with
3-amino-9-ethylcarbazole. After a second blocking step for endogenous
biotin with avidin-biotin, a mouse monoclonal CD1a (IgG2b) Ab was
followed by a purified rat anti-mouse IgG2a/2b (BD Biosciences) and
the mouse alkaline phosphatase-anti-alkaline phosphatase system
(DAKO, Carpinteria, CA). Alkaline phosphatase was developed using Fast
Blue as chromogen (blue color; Vector Laboratories). In control
sections one of the two primary Abs was omitted.
Statistical analysis
Results were expressed as the mean ± SEM of n separate experiments. Differences between cytokine-treated groups and the control group were compared with the Wilcoxon test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-7, and TNF- on MIP-3 production by RA
synoviocytes
To reproduce the inflammatory situation found in RA synovium, we
investigated whether the monocyte-derived cytokines IL-1 and
TNF-, and the T cell-derived cytokine IL-17, could enhance MIP-3
production by synoviocytes. These cells were incubated with increasing
concentrations of IL-1, TNF-, and IL-17, used alone. After
72 h of culture, supernatants were collected and assayed for
MIP-3 production by ELISA. When IL-17 and TNF- at concentrations
ranging from 0.01 to 1000 ng/ml and IL-1 at concentrations ranging
from 0.01 to 1000 pg/ml were used alone, MIP-3 production increased
in a dose-dependent manner (Fig. 1
A). Unstimulated synoviocytes
did not produce MIP-3. At optimal concentrations, IL-1 (100
pg/ml) induced 13 ng/ml MIP-3 production, while TNF- (100 ng/ml)
and IL-17 (100 ng/ml) had a much lesser effect (4 and 1 ng/ml; Fig. 1A).
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, TNF-, and IL-17 were combined, an enhancing effect
greater than that seen with one cytokine alone was observed. To remain
in the concentration range that could reflect the in vivo situation,
experiments were performed in the presence of 100-fold lower
concentrations of IL-1 (1 pg/ml) and TNF- and IL-17 (1 ng/ml).
With TNF- combined with IL-17 or IL-1, synoviocytes produced much
more MIP-3 than the sum of MIP-3 production with each cytokine
alone, indicating a clear synergistic effect (Fig. 1
B). This
synergistic effect was further enhanced with the combination of three
cytokines. In time-course studies this enhancing effect was seen as
early as 12 h of culture (data not shown). This effect was not
observed when IL-17 was combined with IL-1.
Regulation by IL-4, IL-13, and IL-10 of MIP-3 production by RA
synoviocytes induced by IL-1, TNF-, and IL-17
As IL-4, IL-13, and IL-10 have been defined as
anti-inflammatory cytokines (25, 28, 29), they were
tested for their effects on the secretion of MIP-3 by synoviocytes
stimulated with optimal concentrations of IL-1, TNF-, and IL-17
alone. Levels measured after 72 h of culture are presented in Fig. 1C. Addition of IL-4, IL-13, and IL-10 alone at the onset of
culture had no effect on spontaneous MIP-3 secretion. When combined
with the proinflammatory cytokines, IL-4 and IL-13 reduced MIP-3
production. The effect was particularly pronounced with
TNF--stimulated cells. In contrast, IL-10 had no effect on such
MIP-3 production.
MIP-3 is spontaneously secreted by RA synovium
We have previously shown that explants of whole RA synovial tissue
in ex vivo cultures produce spontaneously high amounts of IL-1,
TNF-, and IL-6 (25). Thus, we measured the spontaneous
production of MIP-3 in the same ex vivo model. As control, we used
samples of OA synovium.
Explants of synovium were cultured for 7 days, supernatants were
collected, and levels of MIP-3 were measured. Levels of MIP-3
produced by synovium explants were 12.8 ± 1.9 ng/ml (range,
0–20; n = 39) for RA and much lower for OA (5.3
± 1.3 ng/ml; range, 0–42; n = 29; p
< 0.005; Fig. 2A).
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was studied in five RA and two OA synovium samples using
RT-PCR techniques followed by Southern blot analysis with specific
probes. MIP-3 mRNA could be detected in four of five RA samples
(Fig. 2B, lanes 3–7) and in none of the OA
samples (Fig. 2B, lanes 1 and 2).
Actin was used as an internal control for gene expression.
MIP-3-producing cells are present in RA synovium
To investigate the presence of MIP-3-producing cells,
immunostaining of RA synovium sections was performed with an
anti-MIP-3 polyclonal Ab. As shown in Fig. 3, cells stained positively for MIP-3
were synoviocytes and were localized in the lining layer (A)
and, to a lesser extet, in the lymphocyte aggregates (B). A
similar staining pattern was observed in synoviocytes stimulated with
IL-1, TNF-, or IL-17 (data not shown). Double staining with
anti-CD1a Ab, a marker of immature DC, showed a close association
between MIP-3-producing cells and CD1a-positive immature DC (Fig. 3C).
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, TNF-, and IL-17 induce MIP-3 production by RA
synovium
The effects of exogenous IL-1, TNF-, and IL-17 were analyzed
on MIP-3 production by RA synovium explants. Samples from three
patients were cultured in the presence of 50 ng/ml TNF- and IL-17 or
100 pg/ml IL-1. Addition of IL-1 increased MIP-3 production by
70% and was more potent than IL-17 (15%; Fig. 4).
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production by a mean of
60%. With some samples, IL-17 soluble receptor showed a particularly
striking inhibitory effect. The maximal effect was observed when the
three receptors were combined, which reduced MIP-3 levels by a mean
of 95% (Fig. 5).
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production by RA synovium is inhibited by IL-4 and
IL-13
The anti-inflammatory cytokines IL-4, IL-13, and IL-10 have
been found to inhibit the production of the monocyte-derived cytokines
IL-1 and TNF- and the T cell-derived cytokine IL-17 by RA
synovium explants (25, 31). Using the same assay system,
we investigated whether the same effect was observed for MIP-3.
Accordingly, synovium explants from four RA patients were cultured with
or without 50 ng/ml IL-4, IL-10, or IL-13. Such concentrations were
previously found to be optimal to inhibit proinflammatory cytokine
production by synovium samples (22, 26). After 7 days the
supernatants were collected and assayed for MIP-3. IL-4 and IL-13
inhibited RA synovium production of MIP-3 by 53 and 48%,
respectively (Fig. 6). In contrast, IL-10
had a very modest or no effect on such production, whereas it was able
to reduce IL-6 production in the same supernatants (data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MIP-3 was found to induce migration of immature DC, NK, and T cells,
but not that of monocytes (10, 12, 36, 37). In this study
we demonstrate that RA synovium was able to produce significant
quantities of MIP-3 in ex vivo cultures, while OA synovium produced
much lower levels. Next we investigated the localization of MIP-3 in
RA synovium. Immunostaining of RA synovium with anti-MIP-3
localized the positive cells in the lining layer and to a lesser extent
in the lymphocyte aggregates. In addition, immature DC, defined by CD1a
expression, were found at the same sites of MIP-3 expression.
Furthermore, our preliminary results indicate an accumulation of
immature DC over mature DC in RA synovium in association with the local
expression of MIP-3 (38). In vitro studies confirmed
synoviocytes as a major source of MIP-3. Such production could be
involved in the trafficking of T cells and immature DC from blood to
the inflammatory site, leading to proper cell positioning and cell-cell
interactions.
Lymphoid follicle formation is also observed in chronic inflammatory
sites, considered ectopic lymphoid organs. Indeed, RA synovium has been
described as such a structure. Such an organization could contribute to
Ag presentation in situ, to clonal expansion of Ag-specific B and T
cells, and to inflammation chronicity (39). Although the
synovial inflammatory microenvironment is associated with the
recruitment of immature DC, it is unclear whether full DC maturation
can be achieved. Lindhout et al. (40) reported that
synoviocytes stimulated with TNF- and IL-1 had intrinsic
properties of follicular DC, which are characteristic of germinal
centers.
The maintenance of an inflammatory infiltrate requires a distorted balance among leukocyte recruitment, retention, proliferation, and death. The failure of synovial T cell apoptosis coupled to an enhanced recruitment would lead to an accumulation of these cells within the rheumatoid synovium. The active retention of T cells, particularly the Th1 subset, by chemokine-driven mechanisms further contributes to their accumulation within the synovial compartment. Thus, inflammation in RA appears to persist as a direct result of sustained recruitment, retention, and survival of T cells mediated by stromal-derived factors associated with the inflamed synovial joint itself.
Recently, numerous studies have suggested a major involvement of T
cells in RA pathogenesis, in particular with the demonstration of the
presence of Th1 cells expressing IL-17. IL-17 shares mainly properties
with IL-1 and TNF-. The three cytokines activate the common
transcription factor NF-
B in a variety of cell types. They all
stimulate stromal cells such as dermal and synovial fibroblasts,
endothelial cells, and epithelial cells to secrete IL-6, IL-8, and
prostaglandin E2 (41, 42).
The present results extend these concepts to chemokines. Interactions
among these three cytokines further amplify these effects. Indeed,
combination of IL-17 with IL-1 or TNF- often leads to synergistic
or additive effects (41, 42). The present study
demonstrates the potency of IL-17, IL-1, and TNF- alone and,
moreover, in combination to induce MIP-3 synthesis by synoviocytes
and synovium. IL-1 was the most powerful inducer of MIP-3, and
addition of IL-17 to TNF- was synergistic. Furthermore, the
combination of these cytokines significantly increases its production.
It is of interest to link IL-17, a T cell cytokine that induces
MIP-3, a chemokine that recruits CD4+ memory T
cells. This interaction could sustain inflammatory processes within the
joint and amplify the involvement of T cells in the pathogenesis of RA.
Conversely, blocking of IL-17 was associated with a profound inhibition
of MIP-3 production, contrasting with the poor inducing effect of
IL-17 used alone on synoviocytes. Such a degree of inhibition may
result from the additive or synergistic interactions commonly observed
between IL-1, TNF, and IL-17 (25).
Regarding the respective contributions of IL-17, IL-1, and TNF-
to RA pathogenesis, their control with specific or nonspecific
inhibitors may lead to a therapeutic anti-inflammatory effect. The
single addition of a soluble receptor reduced MIP-3 release. A
better effect was observed with the combination of three receptors,
confirming the interactions among these factors. The Th2 cytokines,
IL-4, IL-13, and IL-10, have been classified as anti-inflammatory
on the basis of their inhibitory effect on the production of IL-1,
TNF-, IL-6, and IL-8 by monocytes and, moreover, synovium targets
(25, 28, 29). We studied their effects on the production
of MIP-3 by RA synoviocytes stimulated with IL-1, TNF-, and
IL-17. Both IL-4 and IL-13 were also able to inhibit the production of
MIP-3 by RA synovium and cytokine-stimulated synoviocyte. Not all
cytokines classified as anti-inflammatory were able to block
MIP-3 production; in particular, addition of IL-10 had no effect on
the production of MIP-3 by RA synovium and RA synoviocytes
stimulated with cytokines. This finding could be related to the
elevated levels of endogenous IL-10 locally produced by synovium
monocytes (29, 43). In keeping with this, IL-10 was found
previously to have no effect on LIF or IL-6 production by isolated
synoviocytes (26).
The present study shows that blocking the effects of IL-1, TNF-,
and IL-17 at a specific level with a soluble receptor as well at a
broader level with Th2 cytokines inhibited not only the proinflammatory
properties of synovium cells, but also the potential recruitment
pattern induced by these cells. Such blocking reduced the production of
a chemokine known to attract both DC and T cells involved in
inflammation. Our observations suggest that MIP-3 plays a role in
mediating inflammatory process by its ability to chemoattract immature
DC and T cells. Accordingly, this chemokine may represent a target for
RA treatment, using cytokine-specific or nonspecific inhibition.
Conversely, induction of full DC differentiation may favor better
control of the inflammatory process and the causative agent.
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Acknowledgments |
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Abs. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Pierre Miossec, Departments of Immunology and Rheumatology, Hôpital Edouard Herriot, Clinical Immunology Unit, 69437 Lyon, Cedex 03, France. E-mail address: miossec{at}laennec.univ-lyon1.fr
3 Abbreviations used in this paper: RA, rheumatoid arthritis; DC, dendritic cell; MIP, macrophage inflammatory protein; OA, osteoarthritis.
Received for publication February 26, 2001. Accepted for publication August 8, 2001.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
: a novel chemotactic cytokine for macrophages in rheumatoid arthritis. J. Clin. Invest. 93:921.
production by synovial T cells. Clin. Exp. Immunol. 101:398.[Medline]
from lung dendritic cells. J. Exp. Med. 186:825. is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J. Exp. Med. 192:705./CCL20 and CC chemokine receptor 6 in psoriasis. J. Immunol. 164:6621./LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int. J. Cancer 81:650.[Medline]
/CCL20 by epidermal keratinocytes and its role in atopic dermatitis. Int. Immunol. 13:95. from normal and transformed cells. J. Immunol. 165:4470. transgene attracts dendritic cells to established murine tumors and suppresses tumor growth. J. Clin. Invest. 105:1383.[Medline]
, MIP-3, and secondary lymphoid organ chemokine. J. Exp. Med. 191:1381. and interleukin-1 to type I and type II interleukin-1 receptors. J. Biol. Chem. 268:2513. blockade with IL-1 and IL-17 blockade is more effective to control synovial inflammation and bone resorption in an ex vivo model. Arthritis Rheum. 44:1293.[Medline]
and is highly expressed in human dendritic cells. J. Exp. Med. 186:837., MIP-3 and fractalkine induce the locomotion and the mobilization of intracellular calcium, and activate the heterotrimeric G proteins in human natural killer cells. Immunology 95:618.[Medline]
-producing cells in rheumatoid synovium.
Arthritis Rheum. 43(Suppl.):S69 (Abstr.).
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 V. Deleuze, J. Lefort, M. F. Bureau, D. Scherman, and B. B. Vargaftig LPS-induced bronchial hyperreactivity: interference by mIL-10 differs according to site of delivery Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L98 - L105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nonomura, H. Kohsaka, K. Nagasaka, and N. Miyasaka Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis J. Immunol., November 1, 2003; 171(9): 4913 - 4919. [Abstract] [Full Text] [PDF]
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P Mukherjee, B Wu, L Mayton, S-H Kim, P D Robbins, and P H Wooley TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis Ann Rheum Dis, August 1, 2003; 62(8): 707 - 714. [Abstract] [Full Text] [PDF]
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|
|
|
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|
 K. Sasaki, T. Tsuji, T. Jinushi, J. Matsuzaki, T. Sato, K. Chamoto, Y. Togashi, T. Koda, and T. Nishimura Differential regulation of VLA-2 expression on Th1 and Th2 cells: a novel marker for the classification of Th subsets Int. Immunol., June 1, 2003; 15(6): 701 - 710. [Abstract] [Full Text] [PDF] |
