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European Cytokine Network

, Volume 29, Issue 1, pp 27–35 | Cite as

TL1A mediates fibroblast-like synoviocytes migration and Indian Hedgehog signaling pathway via TNFR2 in patients with rheumatoid arthritis

  • Mahmoud Al-Azab
  • Jing Wei
  • Xunli Ouyang
  • Abdalkhalig Elkhider
  • Williams Walana
  • Xiaotong Sun
  • Yawei Tang
  • Bing Wang
  • Xia Li
Research Article

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joints inflammation. One of the aggressive characteristics of RA fibroblast-like synoviocytes (FLS) is the tendency for migration in the local environment, which plays a central role in the RA pathogenesis. Tumor Necrosis Factor (TNF)-like cytokine 1A (TL1A) is a member of TNF superfamily, which has a role in autoimmunity and influences the RA-FLS behavior through TNF receptor 2 (TNFR2).We investigated the effect of TNF-like cytokine 1A (TL1A) on RA-FLS migration using patients’ samples. Specifically, we examined the hedgehog signaling pathway which is a key regulator in chondrocyte growth and differentiation. We found that TL1A increased significantly the hedgehog homologue Indian hedgehog (IHH) and its receptor Patched 1, 2 (PTCH 1, 2) in RA-FLS. In addition, TL1A-stimulated RA-FLS promoted significantly IHH protein expression. However, both mRNA and protein levels decreased substantially after blocking TL1A with TNFR2 antagonist. The migratory property of RA-FLS was enhanced after stimulation of RA-FLS with TL1A, but was compromised following TL1A blockage. In conclusion, our study has revealed that TL1A modulated RA-FLS migration and Indian hedgehog signaling pathway using TNFR2.

Keywords

rheumatoid arthritis TNF-like cytokine 1A fibroblast-like synoviocytes Indian hedgehog patched1 2 receptors TNF-receptor2 

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References

  1. 1.
    Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356.CrossRefPubMedGoogle Scholar
  2. 2.
    Arend WP, Firestein GS. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol 2012; 8: 573.CrossRefPubMedGoogle Scholar
  3. 3.
    Vital EM, Emery P. The development of targeted therapies in rheumatoid arthritis. J Autoimmun 2008; 31: 219.CrossRefPubMedGoogle Scholar
  4. 4.
    Filer A. The fibroblast as a therapeutic target in rheumatoid arthritis. Curr Opin Pharmacol 2013; 13: 413.CrossRefPubMedGoogle Scholar
  5. 5.
    Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 2013; 9: 24.CrossRefPubMedGoogle Scholar
  6. 6.
    Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2010; 233: 233.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lefèvre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 2009; 15: 1414.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wang M, Zhu S, Peng W, et al. Sonic hedgehog signaling drives proliferation of synoviocytes in rheumatoid arthritis: a possible novel therapeutic target. J Immunol Res 2014 (ID: 401903, 10 p.).Google Scholar
  9. 9.
    Peng WX, Zhu SL, Zhang BY, et al. Smoothened regulates migration of fibroblast-like synoviocytes in rheumatoid arthritis via activation of Rho GTPase signaling. Front Immunol 2017; 8: 15.Google Scholar
  10. 10.
    Wei F, Zhou J,Wei X, et al. Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage. Osteoarthritis Cartilage 2012; 20: 755.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhang C, Wei X, Chen C, et al. Indian hedgehog in synovial fluid is a novel marker for early cartilage lesions in human knee joint. Int J Mol Sci 2014; 15: 7250.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Daoussis D, Filippopoulou D, Liossis SN, et al. Anti-TNFα treatment decreases the previously increased serum Indian hedgehog levels in patients with ankylosing spondylitis and affects the expression of functional hedgehog pathway target genes. Semin Arthritis Rheum 2015; 44: 646.CrossRefPubMedGoogle Scholar
  13. 13.
    Migone T-S, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 2002; 16: 479.CrossRefPubMedGoogle Scholar
  14. 14.
    Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985; 162: 2163.CrossRefPubMedGoogle Scholar
  15. 15.
    Mück C, Herndler-Brandstetter D, Micutkova L, Grubeck-Loebenstein B, Jansen-Dürr P. Two functionally distinct isoforms of TL1A (TNFSF15) generated by differential ectodomain shedding. J Gerontol A 2010; 65: 1165.CrossRefGoogle Scholar
  16. 16.
    Zhang J, Wang X, Fahmi H, et al. Role of TL1A in the pathogenesis of rheumatoid arthritis. J Immunol 2009; 183: 5350.CrossRefPubMedGoogle Scholar
  17. 17.
    Prehn JL, Thomas LS, Landers CJ, Yu QT, Michelsen KS, Targan SR. The T cell costimulator TL1A is induced by FcγR signaling in human monocytes and dendritic cells. J Immunol 2007; 178: 4033.CrossRefPubMedGoogle Scholar
  18. 18.
    Cassatella MA, da Silva GP, Tinazzi I, et al. Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis. J Immunol 2007; 178: 7325.CrossRefPubMedGoogle Scholar
  19. 19.
    Shih DQ, Kwan LY, Chavez V, et al. Microbial induction of inflammatory bowel disease associated gene TL1A (TNFSF15) in antigen presenting cells. Eur J Immunol 2009; 39: 3239.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Jones GW, Stumhofer JS, Foster T, et al. Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation. J Fed Am Soc Exp Biol 2011; 25: 409.Google Scholar
  21. 21.
    Ma Z, Wang B, Wang M, et al. TL1A increased IL-6 production on fibroblast-like synoviocytes by preferentially activating TNF receptor 2 in rheumatoid arthritis. Cytokine 2016; 83: 92.CrossRefPubMedGoogle Scholar
  22. 22.
    MacEwan DJ. TNF ligands and receptors–a matter of life and death. Br J Pharmacol 2002; 135: 855.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Meylan F, Davidson TS, Kahle E, et al. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 2008; 29: 79.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Aiba Y, Nakamura M. The role of TL1A andDR3in autoimmune and inflammatory diseases. Mediators Inflamm 2013; 2013 (ID: 258164, 9 p.).Google Scholar
  25. 25.
    Arnett FC, Edworthy SM, Bloch DA, et al. The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315.CrossRefPubMedGoogle Scholar
  26. 26.
    Li H, Qin S, Sun D, et al. Sonic hedgehog (SHH) promotes the proliferation of synovial fibroblasts of rats with collagen-induced arthritis. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2016;32:630–4.PubMedGoogle Scholar
  27. 27.
    Li R, Cai L, Ding J, et al. Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis. J Pharm Pharmacol 2015;67:963–71.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhou J, Wei X, Wei L. Indian hedgehog, a critical modulator in osteoarthritis, could be a potential therapeutic target for attenuating cartilage degeneration disease. Connect Tissue Res 2014; 55: 257.CrossRefPubMedGoogle Scholar
  29. 29.
    Yang J, Andre P, Ye L, Yang Y. The hedgehog signalling pathway in bone formation. Int J Oral Sci 2015; 7: 73.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wei F, Zhou J, Fleming BC, et al. Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage. Osteoarthritis Cartilage 2012; 20: 755.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Xiao Q, Hou N, Wang YP, et al. Impaired sonic hedgehog pathway contributes to cardiac dysfunction in type 1 diabetic mice with myocardial infarction. Cardiovasc Res 2012; 95: 507.CrossRefPubMedGoogle Scholar
  32. 32.
    Goetze S, Raessler F, Hipler UC, Schulz S, Kohlhase J, Elsner P. Unexpected manifestation of naevoid basal cell carcinoma (Gorlin) syndrome with a novel mutation in the PTCH1 gene in a female patient with long-lasting pemphigus vulgaris. J Eur Acad Dermatol Venereol 2016; 30: 493–4.CrossRefPubMedGoogle Scholar
  33. 33.
    Shuang F, Zhou Y, Hou S, et al. Indian hedgehog signaling pathway members are associated with magnetic resonance imaging manifestations and pathological scores in lumbar facet joint osteoarthritis. Sci Rep 2015; 5: 10290.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yi J, Zhu Y, Jia Y, et al. The annexin a2 promotes development in arthritis through neovascularization by amplification hedgehog pathway. PLoS ONE 2016; 11: e0150363.Google Scholar
  35. 35.
    Yu Z, Lin W, Rui Z, Jihong Z. Fibroblast-like synoviocyte migration is enhanced by IL-17-mediated overexpression of L-type amino acid transporter 1 (LAT1) via the mTOR/4E-BP1 pathway. Amino Acids 2017. doi: 10.1007/s00726-017-2520-4.Google Scholar
  36. 36.
    Li X-F, Sun Y-Y, Bao J, et al. Functional role of PPAR-γ on the proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis. Sci Rep 2017; 7: 12671. doi: 10.1038/s41598-017-12570-6.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ye Y, Gao X, Yang N. LncRNA ZFAS1 promotes cell migration and invasion of fibroblast-like synoviocytes by suppression of miR-27a in rheumatoid arthritis. Hum Cell 2017. doi: 10.1007/s13577-017-0179-5.Google Scholar
  38. 38.
    Vanamee ÉS, Faustman DL. Structural principles of tumor necrosis factor superfamily signaling. Sci Signal 2018; 2: 11.Google Scholar
  39. 39.
    Fischer R, Proske M, Duffey M, et al. Selective activation of tumor necrosis factor receptor 2 induces anti-inflammatory responses and alleviates experimental arthritis. Arthritis Rheumatol 2018; 17. doi: 10.1002/art.40413.Google Scholar
  40. 40.
    Boissier MC, Semerano L, Challal S, et al. Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. J Autoimmun 2012; 39: 222.CrossRefPubMedGoogle Scholar
  41. 41.
    Turner JD, Filer A. The role of the synovial fibroblast in rheumatoid arthritis pathogenesis. Curr Opin Rheumatol 2015; 27: 175.CrossRefPubMedGoogle Scholar
  42. 42.
    Ganesan R, Rasoo M. Fibroblast-like synoviocytes-dependent effector molecules as a critical mediator for rheumatoid arthritis: current status and future directions. Int Rev Immunol 2017; 36: 20.CrossRefPubMedGoogle Scholar
  43. 43.
    O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 2015; 66: 311.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Li G, Zhang Y, Qian Y, et al. Interleukin-17A promotes rheumatoid arthritis synoviocytes migration and invasion under hypoxia by increasing MMP2 and MMP9 expression through NF-κB/HIF-1α pathway. Mol Immunol 2013; 53: 227.CrossRefPubMedGoogle Scholar

Copyright information

© John Libbey Eurotext 2018

Authors and Affiliations

  • Mahmoud Al-Azab
    • 1
  • Jing Wei
    • 1
  • Xunli Ouyang
    • 1
  • Abdalkhalig Elkhider
    • 1
  • Williams Walana
    • 1
  • Xiaotong Sun
    • 1
  • Yawei Tang
    • 1
  • Bing Wang
    • 1
  • Xia Li
    • 1
  1. 1.Department of Immunology, College of Basic Medical ScienceDalian Medical UniversityLiaoningChina

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