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Engagement of Toll-Like Receptor 3 Induces Vascular Endothelial Growth Factor and Interleukin-8 in Human Rheumatoid Synovial Fibroblasts

  • Moon, Su-Jin (Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine) ;
  • Park, Mi-Kyung (Rheumatism Research Center, Catholic Institute of Medical Science) ;
  • Oh, Hye-Jwa (Rheumatism Research Center, Catholic Institute of Medical Science) ;
  • Lee, Seon-Yeong (Rheumatism Research Center, Catholic Institute of Medical Science) ;
  • Kwok, Seung-Ki (Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine) ;
  • Cho, Mi-La (Rheumatism Research Center, Catholic Institute of Medical Science) ;
  • Ju, Ji-Hyeon (Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine) ;
  • Park, Kyung-Su (Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine) ;
  • Kim, Ho-Youn (Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine) ;
  • Park, Sung-Hwan (Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine)
  • Received : 2010.01.27
  • Accepted : 2010.08.04
  • Published : 2010.12.01

Abstract

Background/Aims: Angiogenesis, which is a critical step in the initiation and progression of rheumatoid arthritis (RA), involves pro-angiogenic factors, including interleukin (IL)-8 and vascular endothelial growth factor (VEGF). We investigated the role of Toll-like receptor 3 (TLR3) in the regulation of pro-angiogenic factors in RA fibroblastlike synoviocytes (FLS). Methods: FLS were isolated from RA synovial tissues and stimulated with the TLR3 ligand, poly (I:C). The levels of VEGF and IL-8 in the culture supernatants were measured using enzyme-linked immunosorbent assays, and the mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction. The expression patterns of VEGF and IL-8 in the RA synovium and osteoarthritis (OA) synovium were compared using immunohistochemistry. Results: The expression levels of TLR3, VEGF, and IL-8 were significantly higher in the RA synovium than in the OA synovium. VEGF and IL-8 production were increased in the culture supernatants of RA FLS stimulated with poly (I:C), and the genes for these proteins were up-regulated at the transcriptional level after poly (I:C) treatment. Treatment with inhibitors of nuclear factor-kappaB (NF-${\kappa}B$), i.e., pyrrolidine dithiocarbamate and parthenolide, abrogated the stimulatory effect of poly (I:C) on the production of VEGF and IL-8 in RA FLS. Conclusions: Our results suggest that the activation of TLR3 in RA FLS promotes the production of proangiogenic factors, in a process that is mediated by the NF-${\kappa}B$ signaling pathway. Therefore, targeting the TLR3 pathway may be a promising approach to preventing pathologic angiogenesis in RA.

Keywords

References

  1. Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 2002;161:125-134. https://doi.org/10.1016/S0002-9440(10)64164-8
  2. Mizukami Y, Jo WS, Duerr EM, et al. Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 2005;11:992-997. https://doi.org/10.1038/nm1294
  3. Kim S, Hagemann A, DeMichele A. Immuno-modulatory gene polymorphisms and outcome in breast and ovarian cancer. Immunol Invest 2009;38:324-340. https://doi.org/10.1080/08820130902910567
  4. Kasama T, Shiozawa F, Kobayashi K, et al. Vascular endothelial growth factor expression by activated synovial leukocytes in rheumatoid arthritis: critical involvement of the interaction with synovial fibroblasts. Arthritis Rheum 2001;44:2512-2524. https://doi.org/10.1002/1529-0131(200111)44:11<2512::AID-ART431>3.0.CO;2-O
  5. Cho ML, Cho CS, Min SY, et al. Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis Rheum 2002;46:1202-1209. https://doi.org/10.1002/art.10215
  6. Flacher V, Bouschbacher M, Verronèse E, et al. Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria. J Immunol 2006;177:7959-7967. https://doi.org/10.4049/jimmunol.177.11.7959
  7. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21:335-376. https://doi.org/10.1146/annurev.immunol.21.120601.141126
  8. Brentano F, Schorr O, Gay RE, Gay S, Kyburz D. RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum 2005; 52:2656-2665. https://doi.org/10.1002/art.21273
  9. Huang Q, Ma Y, Adebayo A, Pope RM. Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum 2007;56:2192-2201. https://doi.org/10.1002/art.22707
  10. Ospelt C, Brentano F, Rengel Y, et al. Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum 2008;58:3684-3692. https://doi.org/10.1002/art.24140
  11. Muzio M, Bosisio D, Polentarutti N, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 2000; 164:5998-6004. https://doi.org/10.4049/jimmunol.164.11.5998
  12. Zare F, Bokarewa M, Nenonen N, et al. Arthritogenic properties of double-stranded (viral) RNA. J Immunol 2004;172:5656-5663. https://doi.org/10.4049/jimmunol.172.9.5656
  13. Kumar MV, Nagineni CN, Chin MS, Hooks JJ, Detrick B. Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J Neuroimmunol 2004;153:7-15. https://doi.org/10.1016/j.jneuroim.2004.04.018
  14. Kim HR, Cho ML, Kim KW, et al. Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase-, NF-kappaB- and p38 MAPK-dependent signalling pathways. Rheumatology (Oxford) 2007;46:57-64. https://doi.org/10.1093/rheumatology/kel159
  15. Izquierdo E, Canete JD, Celis R, et al. Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy. PLoS One 2009;4:e8131. https://doi.org/10.1371/journal.pone.0008131
  16. Koch AE. Angiogenesis as a target in rheumatoid arthritis. Ann Rheum Dis 2003;62 Suppl 2:ii60-ii67.
  17. Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK. Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis 2005;8:63-71. https://doi.org/10.1007/s10456-005-5208-4
  18. Koch AE, Polverini PJ, Kunkel SL, et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 1992;258: 1798-1801. https://doi.org/10.1126/science.1281554
  19. Masood R, Cai J, Tulpule A, et al. Interleukin 8 is an autocrine growth factor and a surrogate marker for Kaposi's sarcoma. Clin Cancer Res 2001;7:2693-2702.
  20. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 2003;170:3369-3376. https://doi.org/10.4049/jimmunol.170.6.3369
  21. Huang Q, Pope RM. Toll-like receptor signaling: a potential link among rheumatoid arthritis, systemic lupus, and atherosclerosis. J Leukoc Biol 2010;88:253-262. https://doi.org/10.1189/jlb.0310126
  22. Meng L, Zhu W, Jiang C, et al. Toll-like receptor 3 upregulation in macrophages participates in the initiation and maintenance of pristane-induced arthritis in rats. Arthritis Res Ther 2010;12:R103. https://doi.org/10.1186/ar3034
  23. Franssila R, Hedman K. Infection and musculoskeletal conditions: viral causes of arthritis. Best Pract Res Clin Rheumatol 2006;20:1139-1157. https://doi.org/10.1016/j.berh.2006.08.007
  24. Bokarewa M, Tarkowski A, Lind M, Dahlberg L, Magnusson M. Arthritogenic dsRNA is present in synovial fluid from rheumatoid arthritis patients with an erosive disease course. Eur J Immunol 2008;38:3237-3244. https://doi.org/10.1002/eji.200838362
  25. Roelofs MF, Wenink MH, Brentano F, et al. Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA). Ann Rheum Dis 2009;68:1486-1493. https://doi.org/10.1136/ard.2007.086421
  26. Holm CK, Petersen CC, Hvid M, et al. TLR3 ligand polyinosinic: polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells. J Immunol 2009;183:4422-4431. https://doi.org/10.4049/jimmunol.0804318
  27. Paone A, Galli R, Gabellini C, et al. Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha. Neoplasia 2010;12:539-549. https://doi.org/10.1593/neo.92106
  28. Kleinman ME, Yamada K, Takeda A, et al. Sequence- and targetindependent angiogenesis suppression by siRNA via TLR3. Nature 2008;452:591-597. https://doi.org/10.1038/nature06765
  29. Kim KW, Cho ML, Oh HJ, et al. TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. Immunol Lett 2009;124:9-17. https://doi.org/10.1016/j.imlet.2009.02.006
  30. Finckh A, Bansback N, Marra CA, et al. Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis. Ann Intern Med 2009;151:612-621. https://doi.org/10.7326/0003-4819-151-9-200911030-00006

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