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Expression of heat shock protein receptors on fibroblast-like synovial cells derived from rheumatoid arthritis-affected joints

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Abstract

We examined the membrane expression of inducible Hsp70 and HSP receptors like TLR2, TLR4, CD14, CD36, CD40 and CD91 on fibroblast-like synovial cells (SC) derived from synovial tissue in 23 patients with rheumatoid arthritis (RA), who underwent synovectomy by using flow cytometric analysis. For comparison, autologous skin fibroblasts (SF) derived from the operation wound were tested. Significantly higher Hsp70 expression was found on synovial cells than on skin fibroblasts (median SC 21.4% × SF 5.0%, P < 0.001). Both synovial cells and skin fibroblasts expressed high levels of cell surface CD91 (median SC 80.2% × SF 79.2%), however, no or low levels of CD14, CD40, TLR2, TLR4 and CD36. Further, we observed high co-expression of CD91 and Hsp70 on RA synovial cells (median 18.6%), while skin fibroblasts showed only background Hsp70 expression (median 3.9%, P < 0.001). Since we demonstrated the high prevalence of inducible Hsp70 in RA synovial fluids, we speculate that Hsp70 might be captured onto the membrane of synovial cells from the extracellular space via the CD91 receptor. The significance of the Hsp70 interaction with synovial cells via CD91 remains undefined, but may mediate other non-immune purposes.

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References

  1. Zlacka D, Vavrincova P, Hien Nguyen TT, Hromadnikova I (2006) Frequency of anti-hsp60, -65 and -70 antibodies in sera of patients with juvenile idiopathic arthritis. J Autoimmun 27:81–88

    Article  PubMed  CAS  Google Scholar 

  2. Nguyen TTH, Gehrmann M, Zlacka D, Sosna A, Vavrincova P, Hromadnikova I (2006) Heat shock protein 70 membrane expression on fibroblast-like synovial cells derived from synovial tissue of patients with rheumatoid and juvenile idiopathic arthritis. Scand J Rheumatol 35:447–453

    Article  PubMed  CAS  Google Scholar 

  3. Schett G, Redlich K, Xu Q, Bizan P, Groger M, Tohidast-Akrad M, Kiener H, Smolen J, Steiner G (1998) Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. J Clin Invest 102:302–311

    Article  PubMed  CAS  Google Scholar 

  4. Martin CA, Carsons SE, Kowalewski R, Bernstein D, Valentino M, Santiago-Schwarz F (2003) Aberrant extracellular and dendritic cell (DC) surface expression of heat shock protein (hsp) 70 in the rheumatoid joint: possible mechanisms of hsp/DC-mediated cross-priming. J Immunol 171:5736–5742

    PubMed  CAS  Google Scholar 

  5. Haug M, Schepp CP, Kalbacher H, Dannecker GE, Holzer U (2007) 70-kDa heat shock proteins: specific interactions with HLA-DR molecules and their peptide fragments. Eur J Immunol 37:1053–1063

    Article  PubMed  CAS  Google Scholar 

  6. Lipsker D, Ziylan U, Spehner D, Proamer F, Bausinger H, Jeannin P, Salamero J, Bohbot A, Cazenave JP, Drillien R, Delneste Y, Hanau D, de la Salle H (2002) Heat shock proteins 70 and 60 share common receptors which are expressed on human monocyte-derived but not epidermal dendritic cells. Eur J Immunol 32:322–332

    Article  PubMed  CAS  Google Scholar 

  7. Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Muller M, Kreymborg K, Altenberend F, Brandenburg J, Kalbacher H, Brock R, Driessen C, Rammensee HG, Stevanovic S (2005) Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci USA 102:7922–7927

    Article  PubMed  CAS  Google Scholar 

  8. Auger I, Escola JM, Gorvel JP, Roudier J (1996) HLA-DR4 and HLA-DR10 motifs that carry susceptibility to rheumatoid arthritis bind 70-kD heat shock proteins. Nat Med 2:306–310

    Article  PubMed  CAS  Google Scholar 

  9. Maier JT, Haug M, Foll JL, Beck H, Kalbacher H, Rammensee HG, Dannecker GE (2002) Possible association of non-binding of HSP70 to HLA-DRB1 peptide sequences and protection from rheumatoid arthritis. Immunogenetics 54:67–73

    Article  PubMed  CAS  Google Scholar 

  10. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1988) The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  PubMed  CAS  Google Scholar 

  11. Edwars JC (2000) Fibroblast biology. Development and differentiation of synovial fibroblasts in arthritis. Arthritis Res 2:344–347

    Article  Google Scholar 

  12. Seidel MF, Koch FW, Vetter H (2006) Macrophage-like synoviocytes display phenotypic polymorphisms in a serum-free tissue-culture medium. Rheumatol Int 26:244–251

    Article  PubMed  Google Scholar 

  13. Kunisch E, Fuhrmann R, Roth A, Winter R, Lungershausen W, Kinne RW (2004) Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry. Ann Rheum Dis 63:774–784

    Article  PubMed  CAS  Google Scholar 

  14. Farkas B, Hantschel M, Magyarlaki M, Becker B, Scherer K, Landthaler M, Pfister K, Gehrmann M, Gross C, Mackensen A, Multhoff G (2003) Heat shock protein 70 membrane expression and melanoma-associated marker phenotype in primary and metastatic melanoma. Melanoma Res 13:147–152

    Article  PubMed  CAS  Google Scholar 

  15. Tanaka A, O’Sullivan FX, Koopman WJ, Gay S (1988) Etiopathogenesis of rheumatoid arthritis-like disease in MRL/1 mice: II. Ultrastructural basis of joint destruction. J Rheumatol 15:10–16

    PubMed  CAS  Google Scholar 

  16. Geiler T, Kriegsmann J, Keyszer GM, Gay RE, Gay S (1994) A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. Arthritis Rheum 37:1664–1671

    Article  PubMed  CAS  Google Scholar 

  17. Markovic M, Stuhlmeier KM (2006) Short-term hyperthermia prevents activation of proinflammatory genes in fibroblast-like synoviocytes by blocking the activation of the transcription factor NF-kappaB. J Mol Med 84:821–832

    Article  PubMed  CAS  Google Scholar 

  18. Kriegsmann J, Keyszer GM, Geiler T, Brauer R, Gay RE, Gay S (1995) Expression of vascular cell adhesion molecule-1 mRNA and protein in rheumatoid synovium demonstrated by in situ hybridization and immunohistochemistry. Lab Invest 72:209–214

    PubMed  CAS  Google Scholar 

  19. Seemayer CA, Kuchen S, Kuenzler P, Rihoskova V, Rethage J, Aicher WK, Michel BA, Gay RE, Kyburz D, Neidhart M, Gay S (2003) Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis. Am J Pathol 162:1549–1557

    PubMed  CAS  Google Scholar 

  20. Schett G, Tohidast-Akrad M, Steiner G, Smolen J (2001) The stressed synovium. Arthritis Res 3:80–86

    Article  PubMed  CAS  Google Scholar 

  21. Morimoto RI (1990) The stress response, function of the proteins, and perspectives. Stress proteins in biology and medicine. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY

    Google Scholar 

  22. Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B (1997) Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol 17:5317–5327

    PubMed  CAS  Google Scholar 

  23. Schett G, Steiner CW, Groger M, Winkler S, Graninger W, Smolen J, Xu Q, Steiner G (1999) Activation of Fas inhibits heat-induced activation of HSF1 and up-regulation of hsp70. FASEB J 13:833–842

    PubMed  CAS  Google Scholar 

  24. Sugiyama M, Tsukazaki T, Yonekura A, Matsuzaki S, Yamashita S, Iwasaki K (1996) Localisation of apoptosis and expression of apoptosis related proteins in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis 55:442–449

    Article  PubMed  CAS  Google Scholar 

  25. Asahara H, Hasunuma T, Kobata T, Inoue H, Muller-Ladner U, Gay S, Sumida T, Nishioka K (1997) In situ expression of protooncogenes and Fas/Fas ligand in rheumatoid arthritis synovium. J Rheumatol 24:430–435

    PubMed  CAS  Google Scholar 

  26. Calderwood SK, Mambula SS, Gray PJ Jr, Theriault JR (2007) Extracellular heat shock proteins in cell signaling. FEBS Lett 19:3689–3694

    Article  CAS  Google Scholar 

  27. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442

    Article  PubMed  CAS  Google Scholar 

  28. Asea A, Kabingu E, Stevenson MA, Calderwood SK (2000) HSP70 peptide bearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones 5:425–431

    Article  PubMed  CAS  Google Scholar 

  29. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  PubMed  CAS  Google Scholar 

  30. Delneste Y, Magistrelli G, Gauchat J, Haeuw J, Aubry J, Nakamura K (2002) Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity 17:353–362

    Article  PubMed  CAS  Google Scholar 

  31. Binder RJ, Vatner R, Srivastava P (2004) The heat-shock protein receptors: some answers and more questions. Tissue Antigens 64:442–451

    Article  PubMed  CAS  Google Scholar 

  32. Gross C, Hansch D, Gastpar R, Multhoff G (2003) Interaction of heat shock protein 70 peptide with NK cells involves the NK receptor CD94. Biol Chem 384:267–279

    Article  PubMed  CAS  Google Scholar 

  33. Berwin B, Hart JP, Rice S, Gass C, Pizzo SV, Post SR, Nicchitta CV (2003) Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J 22:6127–6136

    Article  PubMed  CAS  Google Scholar 

  34. Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313

    Article  PubMed  CAS  Google Scholar 

  35. Binder RJ, Srivastava PK (2004) Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci USA 101:6128–6133

    Article  PubMed  CAS  Google Scholar 

  36. Wang Y, Kelly CG, Karttunen JT, Whittall T, Lehner PJ, Duncan L, MacAry P, Younson JS, Singh M, Oehlmann W, Cheng G, Bergmeier L, Lehner T (2001) CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15:971–983

    Article  PubMed  CAS  Google Scholar 

  37. Becker T, Hartl FU, Wieland F (2002) CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 158:1277–1285

    Article  PubMed  CAS  Google Scholar 

  38. Tobian AA, Canaday DH, Harding CV (2004) Bacterial heat shock proteins enhance class II MHC antigen processing and presentation of chaperoned peptides to CD4+ T cells. J Immunol 173:5130–5137

    PubMed  CAS  Google Scholar 

  39. Panjwani NN, Popova L, Srivastava PK (2002) Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 168:2997–3003

    PubMed  CAS  Google Scholar 

  40. Theriault JR, Mambula SS, Sawamura T, Stevenson MA, Calderwood SK (2005) Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Lett 579:1951–1960

    Article  PubMed  CAS  Google Scholar 

  41. Tuan TL, Keller LC, Sun D, Nimni ME, Cheung D (1994) Dermal fibroblasts activate keratinocyte outgrowth on collagen gels. J Cell Sci 107:2285–2289

    PubMed  CAS  Google Scholar 

  42. Calderwood SK, Theriault J, Gray PJ, Gong J (2007) Cell surface receptors for molecular chaperones. Methods 43:199–206

    Article  PubMed  CAS  Google Scholar 

  43. Li Z, Menoret A, Srivastava P (2002) Roles of heat-shock proteins in antigen presentation and cross-presentation. Curr Opin Immunol 14:45–51

    Article  PubMed  CAS  Google Scholar 

  44. Li Y, Marzolo MP, van Kerkhof P, Strous GJ, Bu G (2000) The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. J Biol Chem 275:17187–17194

    Article  PubMed  CAS  Google Scholar 

  45. Guzhova I, Kislyakova K, Moskaliova O, Fridlanskaya I, Tytell M, Cheetham M, Margulis B (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 914:66–73

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by TRANSEUROPE, No. QLRT-2001- 01936; Trans-net, No. MRTN-CT-2004-512253 and VZ FNM MZO 00064203.

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Authors and Affiliations

  1. Department of Molecular Biology and Cell Pathology, 3rd Medical Faculty, Charles University, Ruska 87, Prague 10, 10000, Czech Republic

    Ilona Hromadnikova, Thi Thu Hien Nguyen, Denisa Zlacka & Lucie Sedlackova

  2. 1st Clinic of Orthopaedics, University Hospital Motol, First Medical Faculty, Charles University, V Uvalu 84, Prague 5, 15000, Czech Republic

    Stanislav Popelka, David Veigl, Jan Pech & Antonin Sosna

  3. Rheumatology Outpatient Department, University Hospital Motol, V Uvalu 84, Prague 5, 15000, Czech Republic

    Pavla Vavrincova

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  1. Ilona Hromadnikova
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  2. Thi Thu Hien Nguyen
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Correspondence to Ilona Hromadnikova.

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Hromadnikova, I., Nguyen, T.T.H., Zlacka, D. et al. Expression of heat shock protein receptors on fibroblast-like synovial cells derived from rheumatoid arthritis-affected joints. Rheumatol Int 28, 837–844 (2008). https://doi.org/10.1007/s00296-008-0532-9

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  • DOI: https://doi.org/10.1007/s00296-008-0532-9

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