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Department of Bioregulatory Medicine and Rheumatology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan;
Department of Orthopedic Surgery, Osaka University Medical School, Osaka, Japan; and
Inflammation Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamonouchi Pharmaceutical Co., Ltd., Ibaraki, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1
, and TGF-1. Our results
indicate that the chemokines not only play a role in inflammatory cell
migration, but are also involved in the activation of FLS in RA
synovium, possibly in an autocrine or paracrine
manner. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rheumatoid arthritis (RA),3 a chronic inflammatory condition affecting several joints, is characterized by proliferation of synoviocytes in inflamed synovia and expression of inflammatory cytokines and chemokines on synoviocytes (8, 9). Thus, activated synoviocytes seem to contribute to the pathogenesis of RA. Several studies have examined the pathogenic role of chemokine and chemokine receptor interaction in RA (10, 11, 12, 13, 14, 15). For example, CCL2 (formerly named as monocyte chemotactic protein-1) and CCL5 (RANTES) are expressed in RA synovium (10, 11, 12, 13). Furthermore, we and other groups have recently demonstrated overexpression of CXCR4 by CD4+ memory T cells in RA synovium, and that the unique ligand CXCL12 (stromal cell-derived factor-1) is expressed in RA synovium (14, 15). We also found that CXCL12 costimulates CD4+ T cells to induce cytokine production, activation markers, and proliferation (4). These results suggest that chemokines such as CCL2, CCL5, and CXCL12 play important roles in inflammatory cell migration into RA synovium and stimulation of T cells. However, to our knowledge, the function of the chemokines on fibroblast-like synoviocytes (FLS) has not been analyzed.
The present study was designed to explore novel functions of chemokines in the RA synovium. Specifically, we examined the ability of CCL2, CCL5, and CXCL12 to stimulate FLS of RA patients.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Synovial tissues were obtained at surgery from RA patients. Signed consent forms were obtained before the operation. The experimental protocol was approved by the ethics committee of the Tokyo Medical and Dental University. RA was diagnosed according to the American College of Rheumatology criteria (16). The synovial tissue was minced and incubated with 0.3 mg/ml collagenase (Sigma, St. Louis, MO) for 1 h at 37°C in DMEM (Sigma). Partially digested pieces of the tissue were pressed through a metal screen to obtain single-cell suspensions. Primary culture skin fibroblasts were established from healthy skin samples.
FACS analysis
FITC-conjugated anti-CD14 (322A-1, Beckman Coulter, Fullerton, CA) mAb, FITC-conjugated anti-HLA class II (9-49, Beckman Coulter) mAb, anti-CCR2 mAb (48607, 121, R&D Systems, Minneapolis, MN), anti-CCR5 mAb (45531.111; R&D Systems), and anti-CXCR4 mAb (44708.111; R&D Systems) were used. FLS from RA patients were adjusted to 1 x 105 cells, incubated with mAb for 30 min, and rinsed with PBS-3% FCS. To analyze chemokine receptor expression, PE-conjugated goat anti-mouse IgG (Southern Biotechnology Associates, Birmingham, AL) was used as a second Ab and analyzed with a FACSCalibur (BD Biosciences, San Jose, CA).
Cell culture
Cells were maintained in high glucose DMEM with 10% FCS
(Sigma). RA FLS were used for experiments after five passages. CD14 or
HLA class II were not expressed by RA FLS (Fig. 1
), suggesting that macrophages and
dendritic cells were not contained in the FLS.
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, IL-1, or
TGF-1 (R&D Systems). After incubation at 37°C for 24 h the
production of cytokines and chemokines was analyzed as described
below. For Western blot analysis, RA FLS (8 x 105 cells/well) were cultured in 60-mm dishes. The stimulation procedure with CCL2 was same as that described above.
All reagents used in this experiment were certified as endotoxin free by the manufacturers. To confirm it, endotoxin level was measured by a Limulus test kit (Pyrogen; BioWhittaker, Walkersville, MD).
RT-PCR
Total RNA was prepared from RA FLS and primary culture skin
fibroblasts using the RNeasy Total RNA System (Qiagen, Valencia, CA).
The RNA was treated with DNase I (Qiagen). First-strand cDNA was
synthesized using oligo(dT) primers and Superscript II reverse
transcriptase (Life Technologies, Gaithersburg, MD). The amount of cDNA
for amplification was adjusted by the amount of RNA measured by OD
meter and also -actin PCR products. The cDNA was amplified with
primers for CCR2 (5'-TGG GAG TTT TGG TGG AGT CCG AT; 3'-GGG GGA TGT GGC
CTA AGA AGC AT), CCR5 (5'-CTC AGG GAA TGA AGG TGT CAG A; 3'-TGC TAC TGT
TGC ACT CTC CAC AAC T), CXCR4 (5'-GGA CCT GTG GCC AAG TTC TTA GTT;
3'-ACT GTA GGT GCT GAA ATC AAC CCA), and -actin (5'-GTG GGG CGC CCC
AGG CAC CA; 3'-CTC CTT AAT GTC ACG CAC CAT TTC). The PCR conditions
were described previously (14). The PCR products were then
separated by electrophoresis through 1.5% agarose.
Western blot
RA FLS were collected and lysed with extraction buffer (20 mM HEPES, 150 mM NaCl, 1% Triton X-100, 1 mM EDTA, 1 mM PMSF, 10 µg/ml leupeptin, and 10 µg/ml aprotinin). After 30 min at 4°C debris was eliminated by centrifugation at 14,000 rpm for 30 min, and the supernatant was collected. After measurement of protein concentration with a protein assay kit (Bio-Rad, Richmond, CA), cell lysates were mixed with 6x sample loading buffer containing 6% 2-ME and 10% SDS and stored at 4°C until analysis. Twenty micrograms of protein was separated by 10% SDS-PAGE, transferred to polyvinylidene difluoride membranes, and blocked with 0.05% Tween 20 and 5% BSA overnight. The immunoblots were incubated with anti-phospho-specific extracellular signal-related kinase 1/2 (ERK1/2) rabbit polyclonal Ab (0.5 µg/ml; BioSource, Camarillo, CA), anti-pan ERK1/2 rabbit polyclonal Ab (1/500; Santa Cruz Biotechnology, Santa Cruz, CA), anti-phospho-specific p38 rabbit polyclonal Ab (0.5 µg/ml; BioSource), anti-pan p38 rabbit polyclonal Ab (1/500; Santa Cruz Biotechnology), anti-phospho-specific Src rabbit polyclonal Ab (0.5 µg/ml; BioSource), or anti-pan Src rabbit polyclonal Ab (0.5 µg/ml; BioSource) in PBS with 1% BSA for 1 h. Subsequently, the immunoblots were incubated with protein A conjugated with HRP (Amersham Pharmacia Biotech, Piscataway, NJ) for 1 h. All immunoblots were detected by ECL (Amersham Pharmacia Biotech).
ELISA
Cytokine and chemokine concentrations in the culture supernatant were assayed with ELISA kits for IL-6, IL-8, CCL2, and CCL5 (BioSource). The CXCL12 concentration in the culture supernatant was measured by sandwich ELISA using anti-CXCL12 mAb (79018.111, R&D Systems) and biotinylated anti-CXCL12 Ab (R&D Systems).
Statistical analysis
All data were expressed as the mean ± SEM. Differences in cytokine and chemokine expression between groups were examined for statistical significance using Student’s t test. A value of p < 0.05 denoted the presence of a statistically significant difference.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CCR2, one of the receptors for CCL2; CCR5, one of the receptors
for CCL5; and CXCR4, a unique receptor for CXCL12 mRNA expression on RA
FLS and primary culture skin fibroblasts, were analyzed by RT-PCR,
respectively. FLS from all three patients with RA and skin fibroblasts
from two healthy donors expressed significant amounts of mRNAs of CCR2,
CCR5, and CXCR4 (Fig. 2A).
Surface CCR2, CCR5, and CXCR4 expression were also analyzed by FACS.
FLS from all three patients with RA expressed CCR2, CCR5, and CXCR4 on
the cell surface (Fig. 2B).
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FLS from RA patients spontaneously produced IL-6 and IL-8. Culture
with CCL2 enhanced the production of IL-6 and IL-8 by RA FLS in a
dose-dependent manner (Fig. 3). CCL5 and
CXCL12 also enhanced IL-6 and IL-8 production by RA FLS, although
the degree of the enhancement by CCL5 and CXCL12 was less than that by
CCL2, especially when used at 500 ng/ml. Interestingly, CCL5 at 500
ng/ml was less effective than at 50 ng/ml in enhancing IL-6 and IL-8
production. TNF- also enhanced IL-6 production by RA FLS.
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),
suggesting that a significant amount of endotoxin was not contained in
this stimulation procedure. In fact, endotoxin was not detected from
any reagents used in this experiment (data not shown). On the other
hand, PTX, a Gi-coupled protein inhibitor,
partially, but significantly, inhibited CCL2-induced enhancement of
IL-6 production by RA FLS (Fig. 5).
However, PTX did not inhibit TNF--induced enhancement of IL-6
production.
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).
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The mitogen-activated protein (MAP) kinase is known to
be important in cell activation. Phosphorylation of MAP kinase,
including ERK1/2, p38 MAP kinases, and c-Jun amino-terminal kinase
(JNK), induced by culture with CCL2 in RA FLS was analyzed.
Phosphorylation of Src protein tyrosine kinase by CCL2 stimulation was
also analyzed. ERK1/2, p38 MAP kinase, and Src were activated without
any stimulation in RA FLS. Culture with CCL2 enhanced the activation of
ERK1/2, but not that of p38 or Src (Fig. 7A). JNK was not activated
without stimulation, and CCL2 did not induce JNK activation (data not
shown). Enhancement of ERK1/2 activation by culture with CCL2 was
inhibited by PTX, a Gi-coupled protein inhibitor,
and RS-504393, a CCR2 antagonist (Fig. 7B).
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RA FLS spontaneously produced CCL2 and CXCL12. TNF-, IL-1,
and TGF-1 enhanced CCL2 expression by RA FLS, although the degree of
the enhancement by TGF-1 was less than that by TNF- and IL-1
(Fig. 8). CCL5 expression was not
detected on RA FLS under this condition without any stimulation.
However, culture with TNF- and IL-1, but not that with TGF-1,
induced CCL5 expression. CXCL12 expression was enhanced by TGF-1,
but not by TNF- or IL-1 (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1, and TGF-1. Thus, our
results indicate that the chemokines are not only involved in
inflammatory cell migration, but also in the regulation of RA FLS
activation in RA synovium, possibly in an autocrine or paracrine
manner.
Previous studies have shown that CCL2 is expressed in RA synovium
(10, 11) and is thought to induce monocyte migration into
inflamed RA synovium. CCL5 is also detected in RA synovium (12, 13) and is speculated to induce T cell migration into RA
synovium. Furthermore, CXCL12 expression is found in RA synovium
(14, 15) and induces CD4+ memory T
cell accumulation. CCL2, CCL5, and CXCL12 also costimulate T cells
(4, 5, 6). Hence, these chemokines seem to play important
roles in the migration of inflammatory cells into RA synovium and
stimulation of T cells. The present study showed that chemokines
stimulated IL-6 and IL-8 production by RA FLS, and that these
chemokines were expressed on RA FLS in association with their
corresponding receptors. Taken together, it is likely that CCL2, CCL5,
and CXCL12 stimulate FLS to enhance cytokine and chemokine production
in an autocrine or paracrine manner in RA synovium. Moreover, CCL2 and
CCL5 are also expressed by macrophage and T cells, respectively, in RA
synovium (10, 13), suggesting that the expressed
chemokines could be relevant molecules to costimulate RA FLS by
macrophages and T cells in RA synovium. TNF- enhanced IL-6
production by RA FLS more effectively than chemokines. However, since
chemokines bind surface proteoglycans (18), they are
sequestered and presented to target cells at high concentration within
the local microenvironment. Thus, chemokine could contribute to RA FLS
activation.
Interestingly, chemokines showed differential effects on RA FLS. For example, CCL2 stimulated RA FLS more effective than CCL5 and CXCL12. Moreover, stimulation by CCL2 and CXCL12, but not CCL5, was dose dependent. In contrast, high concentrations of CCL5 were less effective for enhancement of IL-6 and IL-8 production. Thus, the chemokines might differentially regulate IL-6 and IL-8 production by FLS in RA synovium. In addition, the sensitivity of RA FLS to produce IL-6 in response to CCL2 and CCL5 was increased compared with that of skin-derived fibroblasts. In this respect, our group has reported increased inducibility of p16INK4a, a cyclin-dependent kinase inhibitor, in RA FLS, but not in normal skin fibroblasts (19). It might therefore be possible that RA FLS, which exist in a proinflammatory milieu, are intrinsically different from skin fibroblasts.
The current results showed that culture with CCL2 enhanced activation of ERK1/2, but not p38 MAP kinase, JNK, and Src. Moreover, enhancement of ERK1/2 activation was inhibited by PTX and RS-504393. Thus, it was suggested that CCL2 enhanced activation of ERK1/2, via CCR2 and Gi-coupled protein and probably activation of ERK1/2 induced IL-6 and IL-8 production by RA FLS. It was reported that ERK1/2 activation was maximum at 30 s after CXCL12 stimulation on CTS cells (20). However, the current data showed that CCL2-induced enhancement of ERK1/2 activation on RA FLS was relatively delayed. In this regard it was reported that treatment of CTS cells with CXCL12 resulted in delayed activation of ERK1/2 under stem cell factor stimulation (20). Thus, it is possible that CCL2 may costimulate RA FLS with other factors expressed by RA FLS.
The current data showed that PTX partially inhibited CCL2-induced IL-6 production by RA FLS. It is possible that CCL2 stimulation may be mediated by both PTX-dependent and -independent pathways on RA FLS. In this regard it was reported that CCL5 stimulation involved both PTX-dependent and -independent pathways on T cells (6).
RA FLS are thought to be involved in the pathogenesis of RA (9, 21, 22). These cells produce several types of cytokines and
chemokines, such as IL-6, IL-8, GM-CSF, G-CSF, vascular endothelial
growth factor, CCL3 (macrophage inflammatory protein-1), CCL2, CCL5,
and CXCL12. IL-6 is an acute phase inflammatory cytokine and augments
erosion of the bone. Blockade of IL-6 signal transduction by
anti-IL-6R mAb can be potentially useful therapeutically in RA
(23). IL-8, which is a CXC chemokine (CXCL8), exhibits
proangiogenic activity and induces blood vessel formation and
angiogenesis (9). IL-8 also displays a chemoattractant
activity for neutrophils and dendritic cells (24, 25).
Thus, IL-6 and IL-8, whose production was up-regulated by chemokines,
might contribute to the development of RA.
It has been demonstrated that stimulation by CCL2 enhances collagen expression on rat lung fibroblasts (26) and matrix metalloproteinase expression on human primary culture skin fibroblasts and a stable fibroblast cell line (27, 28). The present results showed that not only CCL2, but also CCL5 and CXCL12, stimulated FLS of RA patients to produce IL-6 and IL-8. Such stimulation by the chemokines was more effective in RA FLS compared with skin fibroblasts.
It was reported that the expression of CCL2 on RA FLS is up-regulated
by TNF-, IL-1, and TGF-1 (10, 11), and CCL5
expression is up-regulated by TNF- and IL-1 (12).
Our results confirmed the previous studies and also showed that
TGF-1, but not TNF- and IL-1, enhanced CXCL12 production by RA
FLS. Considered together, these results suggest that each cytokine
differentially regulates chemokine expression. Since TNF-, IL-1,
and TGF-1 are expressed mainly on macrophages in RA synovium
(29), it is speculated the cytokines expressed by
macrophages, in turn, stimulate FLS to induce chemokines.
In conclusion, we demonstrated in the present study that CCL2, CCL5, and CXCL12 regulated IL-6 and IL-8 production by RA FLS. Our results suggested that these chemokines not only act as a chemoattractant for inflammatory cells and a costimulator of CD4+ T cells, but also stimulate FLS to induce cytokine and chemokine production by RA synovium. Modulation of the production of these chemokines or their interactions with their receptors could be a new mode of treatment for RA.
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Acknowledgments |
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1,
and Hiroko Yamada and Chieko Aizawa for the excellent technical
support. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Toshihiro Nanki, Department of Bioregulatory Medicine and Rheumatology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: nanki.rheu{at}tmd.ac.jp
3 Abbreviations used in this paper: RA, rheumatoid arthritis; FLS, fibroblast-like synoviocytes; PTX, pertussis toxin; ERK, extracellular signal-related kinase; MAP, mitogen-activated protein; JNK, c-Jun amino-terminal kinase.
Received for publication June 20, 2001. Accepted for publication August 21, 2001.
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chemokines costimulate human T lymphocyte activation in vitro. J. Immunol. 156:2095.[Abstract]
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