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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arthritis Rheum. Author manuscript; available in PMC Apr 1, 2012.
Published in final edited form as:
PMCID: PMC3079365
NIHMSID: NIHMS262343

Characterization of CCL19 and CCL21 in Rheumatoid Arthritis

Abstract

Objective

The aim was to characterize the expression of CCL19 and CCL21 in rheumatoid arthritis (RA) synovial tissue and to examine their regulation and pathogenic role in macrophages and RA synovial tissue fibroblasts.

Methods

Expression of CCL19 and CCL21 was demonstrated in RA and normal (NL) synovial tissues employing immunohistochemistry. CCL19 and CCL21 levels were quantified in fluids from osteoarthritis (OA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA) and RA using ELISA. Regulation of CCL19 and CCL21 expression was determined in RA peripheral blood in vitro differentiated macrophages as well as RA synovial tissue fibroblasts by real-time RT-PCR. CCL19 and CCL21 activated peripheral blood in vitro differentiated macrophages and RA synovial tissue fibroblasts were examined for proangiogenic factor production employing ELISA.

Results

CCL19 and CCL21 were elevated in RA synovial tissue compared to NL controls. Levels of CCL19 and CCL21 were greatly increased in RA and PsA synovial fluid versus OA synovial fluid. In RA macrophages and fibroblasts, expression of CCL19 was increased by LPS, TNF-α and IL-1β stimulation. However, CCL21 expression was modulated by IL-1β in RA fibroblasts as well as TNF-α and RA synovial fluid in RA macrophages. CCL19 and CCL21 activation induced VEGF and Ang-1 production from RA synovial tissue fibroblasts and secretion of IL-8 and Ang-1 from macrophages.

Conclusion

We identify, for the first time, regulators of CCL19 and CCL21 in RA fibroblasts and RA peripheral blood in vitro differentiated macrophages and we document a novel role of CCL19/21 in RA angiogenesis.

Keywords: CCL19, CCL21, RA synovial tissue fibroblast, macrophages and proangiogenic factors

Rheumatoid arthritis (RA) is a chronic systemic disorder characterized by the development of new capillaries that are involved in the infiltration of inflammatory cells that result in synovial hyperplasia and progressive destruction of cartilage and bone. Synovial tissue lining consists of macrophages and fibroblasts that have profound effects in the destructive process in RA via production of proinflammatory cytokines, chemokines and proangiogenic factors (1, 2).

CCL19 and CCL21 and their corresponding receptor CCR7 are involved in organizing the thymic architecture and homing of various subpopulations of T cells and antigen-presenting dendritic cells to lymph nodes (3). CCL19 is expressed in lymph nodes and fibroblastic reticular cells of the T cell rich area, whereas CCL21 is secreted from fibroblastic reticular cells and high endothelial venules (4, 5). Although CCL19 and CCL21 have similar affinity to CCR7, ligation of these chemokines mediates different signaling effects. Previous studies have shown that while CCL19 was chemotactic for RA synovial tissue fibroblasts, CCL21 was unable to attract these cells (6). Consistently, CCL19 activated RA synovial tissue fibroblasts produce VEGF while this effect was not noted with CCL21 stimulation (6).

Expression of CCL19 on lymphatic endothelium induces CCR7+ monocyte/macrophage migration (7) and CCL19 can also synergize with CCL2-mediated monocyte migration (8). CCL19 and CCL21 are also involved in the migration of dendritic cells to lymph nodes and their ability to prime T cells (9).

Previous in vivo studies suggest that CCL19 and CCL21 play an important role in a number of autoimmune diseases such as multiple sclerosis, atherosclerosis and RA. Mice lacking CCL19/CCL21 or their receptor CCR7 were resistant to experimental autoimmune encephalomyelitis (EAE) due to reduced number of TH-17 and TH-1 cells (10). Others have shown that antibodies to CCL19 and CCL21 preserve the ApoE −/− lesion size and foam cell content suggesting that these chemokines play a crucial role in cell trafficking to the site of inflammation (11, 12). Recent studies using murine antigen-induced arthritis in CCR7 deficient mice showed lessened arthritis due to impaired development and organization of tertiary lymphoid tissue indicating the importance of CCR7 and its corresponding ligands in lymphoid neogenesis (13). However, the role of CCL19 and CCL21 in RA angiogenesis is undefined.

This study was performed to characterize the expression pattern of CCL19 and CCL21 in RA synovial tissue and fluid and determining the factors that modulate the expression of these chemokines in RA macrophages and fibroblasts as well as their pathogenic role in RA. Our results demonstrate that CCL19/21 are elevated in RA synovial tissue lining and endothelial cells. These chemokines are also significantly elevated in RA compared to OA synovial fluid. Macrophages from RA synovial fluid demonstrate higher levels of CCL19 and CCL21 compared to RA and NL peripheral blood cells. In RA peripheral blood in vitro differentiated macrophages and RA fibroblasts, CCL19 and CCL21 are differentially modulated by proinflammatory factors and/or RA synovial fluid. These chemokines are capable of inducing proangiogenic factors from cells in the RA joint. In conclusion, this study has documented a novel role for CCL19 and CCL21 in RA pathogenesis. Hence, therapy directed against CCR7 ligation may reduce leukocyte migration by inhibiting angiogenesis in RA.

MATERIALS AND METHODS

Antibodies and immunohistochemistry

The studies were approved by the Northwestern University Institutional Review Board, and all donors gave informed written consent. RA and NL synovial tissues were formalin fixed and paraffin embedded, and sectioned in the pathology core facility of Northwestern University. Synovial tissues were immunoperoxidase-stained using Vector Elite ABC Kits (Vector Laboratories), with diaminobenzidine (Vector Laboratories) as a chromogen. Slides were deparaffinized in xylene for 20 min at room temperature, followed by rehydration by transfer through graded alcohols. Antigens were unmasked by first incubating slides in boiling citrate buffer for 15 min, followed by type II trypsin digestion for 30 min at 37°C. Endogenous peroxidase activity was blocked by incubation with 3% H2O2 for 5 min. Nonspecific binding of avidin and biotin was blocked using an avidin/biotin blocking kit (Vector Laboratories). Nonspecific binding of antibodies to the tissues was blocked by pretreatment of tissues with 5% horse serum. Tissues were incubated with rabbit or goat polyclonal antibodies to human CCL19 or CCL21 (1:100, and 1:67 respectively; R & D Systems, Minneapolis, MN), or an IgG control antibody (Beckman Coulter). Slides were counterstained with Harris hematoxylin and treated with lithium carbonate for bluing. Each slide was evaluated by a blinded observer (1417) (A.M.M.). Tissue sections were scored for lining and endothelial staining (on a 0–5 scale). Cell staining was scored on a 0–5 scale where 0=no staining, 1=few cells stained, 2=some (less than half) cells stained, 3= around half of the cells were stained positively 4= majority or more than half of the cells were positively stained and 5= all cells were positively stained. Scored data were pooled, and the mean ± SEM was calculated in each data group, (n=9–15).

Tissue homogenization

RA, OA and NL synovial tissues were homogenized as described previously (18, 19) in 1 ml of complete Mini protease-inhibitor cocktail homogenization buffer (Roche, Indianapolis, IN) on ice, followed by sonication for 30 seconds. Homogenates were centrifuged and filtered through a 0.45 μm pore size filter before quantifying the levels of CCL19 and CCL21 by ELISA. The final concentration of these chemokines in synovial tissue was normalized to the protein concentration in each tissue.

Cell isolation, culture and procedures

NL and RA peripheral blood and RA synovial fluid mononuclear cells were isolated by Histopaque gradient centrifugation (Sigma-aldrich, St. Louis, MO, USA) as previously described (20, 21). Monocytes/macrophages were isolated from NL and RA peripheral blood or RA synovial fluid employing a negative selection kit (StemCell Technologies, Vancouver, Canada) according to the manufacturers’ instructions. Monocytes were subsequently differentiated to macrophages in 20% FBS RPMI for 7 days. Heparinized SFs were centrifuged at 800 × g at room temperature for 10 minutes to obtain cell-free synovial fluid. Synovial fluids from OA, JIA, PsA and RA were analyzed for CCL19 and CCL21 levels.

Quantification of chemokines and cytokines

Human CCL19, CCL21, VEGF, IL-8 and Ang-1 (R&D Systems, Minneapolis, MN, USA) ELISA kits were used according to the manufacturers’ instructions.

Isolation of RA synovial tissue fibroblasts

Synovial tissue fibroblasts were isolated from fresh RA synovial tissues by mincing and digestion in a solution of dispase, collagenase, and DNase (21). Cells were used between passages 3 and 9 and cultured in 10% FBS DMEM.

Cell treatment

RA peripheral blood in vitro differentiated macrophages and RA synovial tissue fibroblasts were treated with LPS (Sigma, 10 ng/ml), TNF-α (R&D Systems, 10 ng/ml), IL-1β (R&D Systems, 10 ng/ml), IL-17 (R&D Systems, 50 ng/ml), IL-6 (R&D Systems, 10 ng/ml), IL-8 (R&D Systems, 10 ng/ml) or RA synovial fluid (1:4 dilution). Cells were harvested after 6 h and the CCL19 and CCL21 mRNA levels were quantified by real-time RT-PCR. RA synovial tissue fibroblasts, normal peripheral blood in vitro differentiated macrophages or human microvascular endothelial cells (HMVECs) were treated with CCL19 (R&D Systems, 10 ng/ml) or CCL21 (R&D Systems, 10 ng/ml) and the cell-conditioned media was harvested following 24 or 48 h treatment.

Real-time RT-PCR

Total cellular RNA was extracted using TRIzol (Invitrogen, Carlsbad, CA) from the different cell types. Subsequently, reverse transcription and real-time RT-PCR were performed to determine CCL19 and CCL21 expression level as described previously (2022). Relative gene expression was determined by the ΔΔCt method, and results were expressed as fold increase above conditions indicated in the figure legends.

Statistical analysis

The data were analyzed using two-tailed Student t tests for paired and unpaired samples. Values of p < 0.05 were considered significant.

RESULTS

CCL19 and CCL21 are elevated in RA synovial tissues

RA and NL synovial tissues were stained with antibodies against CCL19 and CCL21 in order to characterize their expression pattern in RA patients compared to NL individuals. We found that CCL19 (Fig. 1A–C) and CCL21 (Fig. 1D–F) expression were significantly increased in RA synovial tissue lining and endothelial cells compared to NL synovial tissue. Consistently, synovial tissue lining and endothelial cells were positively stained for CCR7 and the immunostaining was greatly higher (p<0.05) in RA compared to NL synovial tissues (data not shown). Since CCR7 and its ligands are coexpressed on the same cell types, this suggests that cells producing these chemokines may be responsive to their activation. Further, upregulation of CCL19 and CCL21 on endothelial cells may play an important role in mediating transendothelial migration.

Figure 1
CCL19 and CCL21 expression is increased in RA synovial tissue (ST) lining and endothelial cells compared to NL ST

NL and OA synovial tissues have significantly lower expression levels of CCL19 and CCL21 compared to RA synovial tissues

Next, CCL19 and CCL21 expression levels were quantified by ELISA and compared among RA, OA and NL synovial tissues. Our results demonstrate that CCL19 expression levels were 3 fold higher in RA synovial tissues compared to OA and NL synovial tissues and both OA and NL synovial tissues had similar CCL19 expression levels (Fig. 2A). Although the highest concentration of CCL21 was detected in RA synovial tissues, unlike CCL19, CCL21 levels were 2 fold higher in OA synovial tissues compared to NL synovial tissues (Fig. 2B). Levels of CCL21 were generally higher in RA and OA synovial tissues compared to CCL19. However, NL synovial tissues had similar levels of CCL19 and CCL21. In conclusion, expression of CCL19 and CCL21 is much higher in RA patients compared to normal individuals.

Figure 2
Expression of CCL19 and CCL21 is higher in RA ST and synovial fluid (SF) compared to OA ST and SF

Synovial fluids from RA and PsA express higher levels of CCL19 and CCL21 compared to those of OA

Levels of CCL19 and CCL21 were compared in RA synovial fluids to synovial fluids obtained from other rheumatic diseases. The data demonstrate that both CCL19 (Fig. 2C) and CCL21 (Fig. 2D) are upregulated in RA (2.5 and 1.5 fold respectively) and PsA synovial fluids (2 and 1.6 fold respectively) compared to OA synovial fluids. Levels of CCL19 and CCL21 were comparable in OA and JIA synovial fluids. While RA synovial tissues had higher levels of CCL21, CCL19 levels are significantly greater (p<0.0005) in RA synovial fluids compared to CCL21. Our results suggest that CCR7 ligands are greatly increased in RA synovial tissue and fluid. Hence, these chemokines may play an important role in the pathogenesis of RA.

Proinflammatory factors upregulate expression of CCL19 and CCL21 in RA synovial tissue fibroblasts

Based on our histological data, we asked whether expression of CCL19 and CCL21 was elevated in RA compared to NL synovial tissue fibroblasts. Results obtained from real-time RT-PCR demonstrate that both CCL19 (Fig. 3A) and CCL21 (Fig. 3B) expression was 4 fold greater in RA compared to NL fibroblasts. We next show that while LPS, TNF-α, and IL-1β upregulates the expression of CCL19 in RA fibroblasts, stimulation with IL-17, IL-6, IL-8, and RA synovial fluid had no effect on this process (Fig. 3C). In RA fibroblasts, expression of CCL21 was only increased by IL-1β activation and other proinflammatory factors were ineffective (Fig. 3D). These results suggest that although both CCL19 and CCL21 are elevated in RA fibroblasts, their expression is differentially regulated.

Figure 3
RA ST fibroblasts have elevated levels of CCL19 and CCL21 which are modulated by proinflammatory factors

Expression levels of CCL19 and CCL21 in cells obtained from peripheral blood and synovial fluid

Since expression levels of CCL19 and CCL21 were elevated in RA synovial tissue lining, which consists of RA synovial tissue fibroblasts and macrophages, we asked whether expression of these chemokines was increased in RA peripheral blood and synovial fluid macrophages compared to normal peripheral blood monocytes and macrophages. Concentrations of CCL19 were significantly higher in RA synovial fluid macrophages compared to RA (146-fold higher in RA SF macrophages) and normal peripheral blood in vitro differentiated macrophages (73-fold higher in RA SF macrophages) employing real-time RT-PCR (Fig. 4A). RA peripheral blood monocytes (6 fold higher than NL peripheral blood monocytes) and macrophages (2 fold higher than NL peripheral blood macrophages) had elevated levels of CCL21 compared to their normal counterparts (Fig. 4B). Further RA synovial fluid macrophages express higher levels of CCL21 compared to RA (2.5 fold) and NL (6 fold) peripheral blood macrophages. Our results suggest that RA synovial fluid macrophages may be an important source for CCL19 and CCL21 production.

Figure 4
CCL19 and CCL21 are upregulated in RA SF macrophages compared to RA and NL peripheral blood (PB) macrophages and proinflammatory factors induce the expression of these chemokines in RA PB in vitro differentiated macrophages

Proinflammatory factors regulate expression of CCL19 and CCL21 in RA macrophages

To determine which factors modulate expression of CCL19 and CCL21 in RA peripheral blood in vitro differentiated macrophages, cells were either untreated or treated with LPS, TNF-α, IL-1β, IL-17, IL-6, IL-8, and RA synovial fluid. Our results demonstrate that CCL19 expression was greatly induced by LPS (145-fold), TNF-α (43-fold), IL-1β (82-fold) and IL-8 (12-fold) activation of RA macrophages compared to untreated cells (Fig. 4C). However only TNF-α (6.5-fold) and RA synovial fluid stimulation (6-fold) upregulated levels of CCL21 in macrophages compared to untreated cells (Fig. 4D). Our results suggest that expression levels of CCL19 and CCL21 are differentially modulated in RA macrophages and that CCL19 is more responsive to stimuli.

CCL19 and CCL21 induce production of proangiogenic factors from RA synovial tissue fibroblasts and macrophages

To examine the mechanism by which CCL19 and CCL21 mediate pathogenesis in RA, CCL19 and CCL21 activated macrophages, RA synovial tissue fibroblasts and HMVECs were screened for proinflammatory factors. CCL19 and CCL21 induced the production of VEGF from RA synovial tissue fibroblasts (Fig. 5A) and IL-8 from macrophages (Fig. 5B) as well as Ang-1 from RA synovial tissue fibroblasts (Fig. 5C) and macrophages (Fig. 5D). However, CCL19 and CCL21 were unable to induce production of IL-6, CCL2/MCP-1, CCL3/MIP-1α, or Ang-2 from RA synovial tissue fibroblasts or macrophages. Further production of TNF-α and IL-1β in macrophages was not mediated by CCL19 and CCL21 stimulation. CCL19 and CCL21 stimulation in HMVECs did not result in production of any proangiogenic factor. These results indicate that the pathogenic role of CCL19 and CCL21 in RA is mediated through production of proangiogenic factors.

Figure 5
CCL19 and CCL21 activate production of proangiogenic factors from macrophages and RA ST fibroblasts

DISCUSSION

In this study, we show that the synovial tissue lining and endothelium in RA patients express higher levels of CCL19 and CCL21 compared to tissues of normal controls. Consistently, RA synovial tissue and fluid have elevated levels of CCL19 and CCL21 compared to OA synovial tissue and fluid. Our data demonstrate that macrophages are an important source of CCL19 and CCL21 production in RA synovial fluid, and levels of these chemokines are greatly upregulated in RA synovial fluid compared to RA and NL peripheral blood macrophages. CCL19 and CCL21 expression levels were also elevated on RA compared to NL fibroblasts. We further show that while CCL19 expression was modulated similarly in RA macrophages and fibroblasts, expression of CCL21 was differentially regulated in these cell types. Last, we demonstrate that CCL19 and CCL21 can activate key proangiogenic factors from macrophages and RA synovial tissue fibroblasts. Our results suggest that ligation of CCR7 by CCL19 and CCL21 can activate angiogenesis in RA.

Previous studies have shown that CCR7 and CCL21 are localized in lymphocytic infiltrates and dendritic cells of RA synovial tissue and play an essential role in maturation and homing of dendritic cells to lymphocytic aggregates (23). Others have shown that CCL19 is produced in mice by fibroblastic cells in lymph nodes, whereas CCL21 is mainly secreted from high endothelial venules (4, 5). In this study we report novel data that CCL19 and CCL21 are coexpressed on the endothelium and RA synovial tissue lining, where macrophages and RA fibroblasts are in close proximity and interact with each other. Since CCL19 and CCL21 and their receptor, CCR7 (data not shown), are present on all three cell types, this may suggest that these cells can be directly activated through ligation. Activation of macrophages and RA fibroblasts by CCL19 and CCL21 may be important for production of proinflammatory factors in the synovium. Further, expression of these chemokines on the vessel walls may play a role in facilitating transendothelial migration of CCR7+ cells.

Angiogenesis is an early and critical event in the pathogenesis of RA (2) and PSA (24) which promotes ingress of leukocytes and pannus formation. Since angiogenesis does not play a vital role in the pathogenesis of OA, CCL19 and CCL21 levels are significantly lower in OA synovial fluid compared to synovial fluid from RA and PSA patients suggesting that these factors may contribute to RA and PSA neovascularization.

RA synovial fluid macrophages had the highest levels of CCL19 and CCL21 expression compared to RA and NL peripheral blood macrophages. While CCL19 expression levels were similar in RA and NL peripheral blood monocytes, CCL21 concentration was significantly higher in RA peripheral blood monocytes compared to NL cells. Interestingly, the expression and function of CCL19 and CCL21 in RA macrophages has not been described. Previous studies have shown that monocytes activated with prostaglandin E express higher levels of CCR7 compared to unstimulated cells, which allows the cells to migrate towards CCL19 and CCL21 (25). A recent study also demonstrates that CCL19 is a chemoattractant for both dendritic cells and monocytes (26). Conversely, others have shown that in the presence of CCL19 and CCL21, monocytes can migrate toward lower concentration of CCL2/MCP-1; however, these chemokines were unable to induce monocyte migration alone (8).

Since fibroblasts and macrophages in RA synovial tissue express CCL19 and CCL21, our next experiments were performed to determine the factors that modulate expression of CCL19 and CCL21 in these cells. We found that in RA synovial tissue fibroblasts, CCL19 expression is induced by LPS, TNF-α, and IL-1β stimulation, whereas CCL21 expression is modulated by IL-1β activation. Interestingly, RA peripheral blood differentiated macrophages responded similarly to RA fibroblasts in that LPS, TNF-α, and IL-1β but not RA synovial fluid were able to regulate the expression of CCL19. In contrast, CCL21 expression levels were differentially regulated in RA macrophages by TNF-α and RA synovial fluid compared to RA fibroblasts which were activated by IL-1β. Since TNF-α and RA synovial fluid activated RA macrophages express comparable levels of CCL21, TNF-α may be one of the major factors present in RA synovial fluid that mediates this effect. These results suggest that the expression of the CCR7 ligands are differentially modulated in the cells types present in the RA synovial tissue lining layer.

Others have shown that lymphotoxins (LTα and LTβ) induce production of CCL19 and CCL21 from the stromal cells within the T cell zones through activation of the NF-κB pathway (27). Further, CCL19 and CCL21 expression was induced by LPS in mouse iris (28). Results from previous studies suggest that activation of TLRs through NF-κB can directly or indirectly modulate the expression CCL19 and CCL21 in the inflammatory site.

Next the pathogenic role of CCL19 and CCL21 was studied in RA fibroblasts, macrophages and endothelial cells. Although activated cells were screened for a variety of inflammatory factors, our results demonstrate that CCL19 and CCL21 were able to induce production of VEGF and Ang-1 from RA synovial tissue fibroblasts and secretion of IL-8 and Ang-1 from macrophages. Production of potent proangiogenic factors from lining cells activated by CCL19 and CCL21 is in line with the role of CCR7 in tumor cell invasion and metastasis. Cyclooxygense (COX)-2 and hypoxia inducible factor (HIF)-1 have been shown to induce CCR7 expression in breast (29, 30) and lung (31) tumor cells, which facilitates their metastasis to lymph nodes where CCL19 and CCL21 are abundantly expressed. The data presented in this study highlight the importance of CCR7 and its ligands in the pathogenesis of RA.

In conclusion, CCL19 and CCL21 are elevated on RA synovial tissue lining and endothelium. Fibroblasts from RA synovial tissue and macrophages from RA synovial fluid and tissue express higher levels of CCL19 and CCL21 compared control cells. Nevertheless the expression of CCL19 and CCL21 is differentially regulated in RA fibroblasts and macrophages. Finally, potent proangiogenic factors are secreted from CCL19 and CCL21 activated RA synovial tissue fibroblasts and macrophages, suggesting that these chemokines play an important role in RA angiogenesis.

Acknowledgments

We are grateful to Sharon Tymkiw and Elizabeth Randall for providing phlebotomy services for RA and NL blood as well as to Brian Zanotti and Nikolay Zlatarov for their technical expertise.

This work was supported in part by awards from the National Institutes of Health (AR056099, AR055240), Arthritis National Research Foundation, grants from Within Our Reach from The American College of Rheumatology and funding provided by Department of Defense PR093477.

Footnotes

AUTHOR CONTRIBUTIONS:

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Shahrara had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Shahrara, Pickens.

Acquisition of data. Pickens, Chamberlain, Volin, Mandelin.

Analysis and interpretation of data. Shahrara, Pickens, Volin, Chamberlain

Providing reagents. Pope

References

1. Szekanecz Z, Koch AE. Mechanisms of Disease: angiogenesis in inflammatory diseases. Nat Clin Pract Rheumatol. 2007;3(11):635–43. [PubMed]
2. Szekanecz Z, Koch AE. Angiogenesis and its targeting in rheumatoid arthritis. Vascul Pharmacol. 2009;51(1):1–7. [PMC free article] [PubMed]
3. Forster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008;8(5):362–71. [PubMed]
4. Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B, et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol. 2007;8(11):1255–65. [PubMed]
5. Carlsen HS, Haraldsen G, Brandtzaeg P, Baekkevold ES. Disparate lymphoid chemokine expression in mice and men: no evidence of CCL21 synthesis by human high endothelial venules. Blood. 2005;106(2):444–6. [PubMed]
6. Bruhl H, Mack M, Niedermeier M, Lochbaum D, Scholmerich J, Straub RH. Functional expression of the chemokine receptor CCR7 on fibroblast-like synoviocytes. Rheumatology (Oxford) 2008;47(12):1771–4. [PubMed]
7. Yamashita M, Iwama N, Date F, Shibata N, Miki H, Yamauchi K, et al. Macrophages participate in lymphangiogenesis in idiopathic diffuse alveolar damage through CCL19-CCR7 signal. Hum Pathol. 2009;40(11):1553–63. [PubMed]
8. Kuscher K, Danelon G, Paoletti S, Stefano L, Schiraldi M, Petkovic V, et al. Synergy-inducing chemokines enhance CCR2 ligand activities on monocytes. Eur J Immunol. 2009;39(4):1118–28. [PubMed]
9. Marsland BJ, Battig P, Bauer M, Ruedl C, Lassing U, Beerli RR, et al. CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity. 2005;22(4):493–505. [PubMed]
10. Kuwabara T, Ishikawa F, Yasuda T, Aritomi K, Nakano H, Tanaka Y, et al. CCR7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells. J Immunol. 2009;183(4):2513–21. [PubMed]
11. Trogan E, Feig JE, Dogan S, Rothblat GH, Angeli V, Tacke F, et al. Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice. Proc Natl Acad Sci U S A. 2006;103(10):3781–6. [PMC free article] [PubMed]
12. Damas JK, Smith C, Oie E, Fevang B, Halvorsen B, Waehre T, et al. Enhanced expression of the homeostatic chemokines CCL19 and CCL21 in clinical and experimental atherosclerosis: possible pathogenic role in plaque destabilization. Arterioscler Thromb Vasc Biol. 2007;27(3):614–20. [PubMed]
13. Wengner AM, Hopken UE, Petrow PK, Hartmann S, Schurigt U, Brauer R, et al. CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 2007;56(10):3271–83. [PubMed]
14. Ruth JH, Volin MV, Haines GK, III, Woodruff DC, Katschke KJ, Jr, Woods JM, et al. Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis. Arthritis and Rheumatism. 2001;44:1568–1581. [PubMed]
15. Koch AE, Nickoloff BJ, Holgersson J, Seed B, Haines GK, Burrows JC, et al. 4A11, a monoclonal antibody recognizing a novel antigen expressed on aberrant vascular endothelium. Upregulation in an in vivo model of contact dermatitis. American Journal of Pathology. 1994;144(2):244–259. [PMC free article] [PubMed]
16. Shahrara S, Proudfoot AE, Woods JM, Ruth JH, Amin MA, Park CC, et al. Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum. 2005;52(6):1907–19. [PMC free article] [PubMed]
17. Shahrara S, Proudfoot AE, Park CC, Volin MV, Haines GK, Woods JM, et al. Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. J Immunol. 2008;180(5):3447–56. [PubMed]
18. Shahrara S, Volin MV, Connors MA, Haines GK, Koch AE. Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue. Arthritis Res. 2002;4(3):201–8. [PMC free article] [PubMed]
19. Shahrara S, Huang Q, Mandelin AM, 2nd, Pope RM. TH-17 cells in rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):R93. [PMC free article] [PubMed]
20. Shahrara S, Pickens SR, Dorfleutner A, Pope RM. IL-17 induces monocyte migration in rheumatoid arthritis. J Immunol. 2009;182(6):3884–91. [PMC free article] [PubMed]
21. Shahrara S, Pickens SR, Mandelin AM, 2nd, Karpus WJ, Huang Q, Kolls JK, et al. IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction. J Immunol. 184(8):4479–87. [PMC free article] [PubMed]
22. Pickens SR, Volin MV, Mandelin AM, 2nd, Kolls JK, Pope RM, Shahrara S. IL-17 contributes to angiogenesis in rheumatoid arthritis. J Immunol. 184(6):3233–41. [PMC free article] [PubMed]
23. Page G, Lebecque S, Miossec P. Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium. J Immunol. 2002;168(10):5333–41. [PubMed]
24. Leong TT, Fearon U, Veale DJ. Angiogenesis in psoriasis and psoriatic arthritis: clues to disease pathogenesis. Curr Rheumatol Rep. 2005;7(4):325–9. [PubMed]
25. Cote SC, Pasvanis S, Bounou S, Dumais N. CCR7-specific migration to CCL19 and CCL21 is induced by PGE(2) stimulation in human monocytes: Involvement of EP(2)/EP(4) receptors activation. Mol Immunol. 2009;46(13):2682–93. [PubMed]
26. Cravens PD, Hayashida K, Davis LS, Nanki T, Lipsky PE. Human peripheral blood dendritic cells and monocyte subsets display similar chemokine receptor expression profiles with differential migratory responses. Scand J Immunol. 2007;65(6):514–24. [PubMed]
27. Schneider K, Potter KG, Ware CF. Lymphotoxin and LIGHT signaling pathways and target genes. Immunol Rev. 2004;202:49–66. [PubMed]
28. Mackensen F, Metea CA, Planck SR, Rosenbaum JT. Endotoxin upregulates CCR7 and its ligands in the lymphatic-free mouse iris. Mol Vis. 2007;13:2209–13. [PubMed]
29. Pan MR, Hou MF, Chang HC, Hung WC. Cyclooxygenase-2 up-regulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells. J Biol Chem. 2008;283(17):11155–63. [PubMed]
30. Wilson JL, Burchell J, Grimshaw MJ. Endothelins induce CCR7 expression by breast tumor cells via endothelin receptor A and hypoxia-inducible factor-1. Cancer Res. 2006;66(24):11802–7. [PubMed]
31. Li Y, Qiu X, Zhang S, Zhang Q, Wang E. Hypoxia induced CCR7 expression via HIF-1alpha and HIF-2alpha correlates with migration and invasion in lung cancer cells. Cancer Biol Ther. 2009;8(4):322–30. [PubMed]
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