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Contribution of Cyclophilin A to the Regulation of Inflammatory Processes in Rheumatoid Arthritis

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Abstract

Introduction

Previous studies show that cyclophilin A (CypA) acts as a strong chemotactic cytokine to neutrophils, eosinophils, and monocytes in rheumatoid arthritis (RA).

Methods

In this study, monocytes were stimulated by purified CypA and the production of matrix metalloproteinase (MMPs), the cell invasion and the release of inflammatory cytokines were detected respectively by gelatin zymography, invasion assay, and cytometric bead array FCM.

Results

The elevated level of inflammatory cytokine IL-8 was also detected. Results showed that CypA significantly promoted the invasion of THP-1 cells and increased the production of MMP-2 and MMP-9, which displayed a biphasic concentration dependency. In vivo experiments found that the cartilage erosion scores in CypA injection group were significantly higher than those in control group (P < 0.05).

Conclusion

Our findings suggest that CypA significantly enhances the secretion of MMP-2 and MMP-9, the cell invasion, and the inflammatory cytokines production of monocytes. Our findings may shed some new light on the inflammatory process and the degradation of cartilage and bone in RA.

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Abbreviations

CypA:

cyclophilin A

CsA:

cyclosporine A

MMP:

matrix metalloproteinase

PCR:

polymerase chain reaction

IPTG:

Isopropyl-β-d-thiogalactopyranoside

Ni–NTA:

Ni-nitrilotriacetic acid

FMLP:

N-Formyl-Met-Leu-Phe

CBA:

cytometric bead array

LPS:

lipopolysaccharide

PMB:

polymyxin B

TNF-α:

tumor necrosis factor α

IL:

interleukin

RA:

rheumatoid arthritis

References

  1. Tarrant TK, Patel DD. Chemokines and leukocyte trafficking in rheumatoid arthritis. Pathophysiology. 2006;13:1–14.

    Article  PubMed  CAS  Google Scholar 

  2. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440.

    Article  PubMed  CAS  Google Scholar 

  3. Arora K, Gwinn WM, Bower MA, Watson A, Okwumabua I, MacDonald HR, et al. Extracellular cyclophilins contribute to the regulation of inflammatory responses. J Immunol. 2005;175:517–22.

    PubMed  CAS  Google Scholar 

  4. Galat A. Peptidylproline cis-trans-isomerases: immunophilins. Eur J Biochem. 1993;216:689–707.

    Article  PubMed  CAS  Google Scholar 

  5. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984;226:544–7.

    Article  PubMed  CAS  Google Scholar 

  6. Saphire AC, Bobardt MD, Gallay PA. Host cyclophilin A mediates HIV-1 attachment to target cells via heparans. EMBO J. 1999;18:6771–85.

    Article  PubMed  CAS  Google Scholar 

  7. Sherry B, Yarlett N, Strupp A, Cerami A. Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages. Proc Natl Acad Sci U S A. 1992;89:3511–5.

    Article  PubMed  CAS  Google Scholar 

  8. Jin ZG, Lungu AO, Xie L, Wang M, Wong C, Berk BC. Cyclophilin A is a proinflammatory cytokine that activates endothelial cells. Arterioscler Thromb Vasc Biol. 2004;24:1186–91.

    Article  PubMed  CAS  Google Scholar 

  9. Kim SH, Lessner SM, Sakurai Y, Galis ZS. Cyclophilin A as a novel biphasic mediator of endothelial activation and dysfunction. Am J Pathol. 2004;164:1567–74.

    PubMed  CAS  Google Scholar 

  10. Billich A, Winkler G, Aschauer H, Rot A, Peichl P. Presence of cyclophilin A in synovial fluids of patients with rheumatoid arthritis. J Exp Med. 1997;185:975–80.

    Article  PubMed  CAS  Google Scholar 

  11. Yao QZ, Li M, Yang H, Chai H, Fisher W, Chen CY. Roles of cyclophilins in cancers and other organ systems. World J Surg. 2005;29:276–80.

    Article  PubMed  Google Scholar 

  12. Giannelli G, Erriquez R, Marinosci F, Lapadula G, Antonaci S. MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in patients with rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol. 2004;22:335–8.

    PubMed  CAS  Google Scholar 

  13. Stawowy P, Meyborg H, Stibenz D, Borges PSN, Roser M, Thanabalasingam U, et al. Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. Circulation. 2005;111:2820–7.

    Article  PubMed  CAS  Google Scholar 

  14. Jia JF, Wang CH, Shi ZG, Zhao JK, Jia Y, Zheng ZH, et al. Inhibitory effect of CD147/HAb18 monoclonal antibody on cartilage erosion and synovitis in the SCID mouse model for rheumatoid arthritis. Rheumatology. 2009;48:721–6.

    Article  PubMed  CAS  Google Scholar 

  15. Seemayer CA, Kuchen S, Kuenzler P, Rihoskova V, Rethage J, Aicher WK. Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis. Am J Pathol. 2003;162:1549–57.

    PubMed  CAS  Google Scholar 

  16. Geiler T, Kriegsmann J, Keyszer GM, Gay RE, Gay S. A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. Arthritis Rheum. 1994;37:1664–71.

    Article  PubMed  CAS  Google Scholar 

  17. Craig EA, Gambill BD, Nelson RJ. Heat shock proteins: molecular chaperones of protein biogenesis. Microbiol Rev. 1993;57:402–14.

    PubMed  CAS  Google Scholar 

  18. Parsell DA, Lindquist S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet. 1993;27:437–96.

    Article  PubMed  CAS  Google Scholar 

  19. Xiang J, Chao DT, Korsmeyer SJ. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc Natl Acad Sci U S A. 1996;93:14559–63.

    Article  PubMed  CAS  Google Scholar 

  20. Sherry B, Zybarth G, Alfano M, Dubrovsky L, Mitchell R, Rich D, et al. Role of cyclophilin A in the uptake of HIV-1 by macrophages and T lymphocytes. Proc Natl Acad Sci U S A. 1998;95:1758–63.

    Article  PubMed  CAS  Google Scholar 

  21. Yurchenko V, Zybarth G, O’Connor M, Dai WW, Franchin G, Hao T, et al. Active site redisues of cyclophilin A are crucial for its signalling activity via CD147. J Biol Chem. 2002;277:22959–65.

    Article  PubMed  CAS  Google Scholar 

  22. Kim H, Kim WJ, Jeon ST, Koh EM, Cha HS, Ahn KS, et al. Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages. Clin Immunol. 2005;116:217–24.

    Article  PubMed  CAS  Google Scholar 

  23. Khromykh LM, Kulikova NL, Anfalova TV, Muranova TA, Abramov VM, Vasiliev AM, et al. Cyclophilin A produced by thymocytes regulates the migration of murine bone marrow cells. Cell Immunol. 2007;249:46–53.

    Article  PubMed  CAS  Google Scholar 

  24. Tchetverikov I, Lard LR, DeGroot J, Verzijl N, TeKoppele JM, Breedveld FC, et al. Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progression in early rheumatoid arthritis. Ann Rheum Dis. 2003;62:1094–9.

    Article  PubMed  CAS  Google Scholar 

  25. Endo H, Akahoshi T, Takagishi K, Kashiwazaki S, Matsushima K. Elevation of interleukin-8 (IL-8) levels in joint fluids of patients with rheumatoid arthritis and the induction by IL-8 of leukocyte infiltration and synovitis in rabbit joints. Lymphokine Cytokine Res. 1991;10:245–52.

    PubMed  CAS  Google Scholar 

  26. Deleuran B, Lemche P, Kristensen M, Chu CQ, Field M, Jensen J, et al. Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chondrocytes in rheumatoid arthritis. Scand J Rheumatol. 1994;23:2–7.

    Article  PubMed  CAS  Google Scholar 

  27. Kraan MC, Patel DD, Haringman JJ, Smith MD, Weedon H, Ahern MJ, et al. The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). Arthritis Res. 2001;3:65–71.

    Article  PubMed  CAS  Google Scholar 

  28. Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, et al. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. Arthritis Res Ther. 2004;6:120–8.

    Article  CAS  Google Scholar 

  29. Ayashida K, Nanki T, Girschick H, Yavuz S, Ochi T, Lipsky PE. Synovial stromal cells from rheumatoid arthritis patients attract monocytes by producing MCP-1 and IL-8. Arthritis Res. 2001;3:118–26.

    Article  Google Scholar 

  30. Eorganas C, Liu H, Perlman H, Hoffmann A, Thimmapaya B, Pope RM. Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun. J Immunol. 2000;165:7199–206.

    Google Scholar 

  31. Takahashi Y, Kasahara T, Sawai T, Rikimaru A, Mukaida N, Matsushima K, et al. The participation of IL-8 in the synovial lesions at an early stage of rheumatoid arthritis. Tohoku J Exp Med. 1999;188:75–87.

    Article  PubMed  CAS  Google Scholar 

  32. Nanki T, Nagasaka K, Hayashida K, Saita Y, Miyasaka N. Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol. 2001;167:5381–5.

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Key Program of the National Natural Science Foundation of China under Grant (No. 30530720) and the National Basic Research Program (No. 2009CB521705).

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

LW participated in the design of the study and drafted the manuscript. CW, one of the co-first authors, conducted the chemotaxis, invasion, gel zymography, and CBA assays; performed the statistical analysis and helped to draft the manuscript. JJ constructed the animal model and performed in vivo assays. XM and YL participated in the construction of the expression vector and the induction of the CypA protein. HZ and HT performed the purification of the CypA. ZC and PZ, the corresponding authors, participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Clinical Immunology, State Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, People’s Republic of China

    Li Wang, Cong-hua Wang, Jun-feng Jia & Ping Zhu

  2. Department of Cell Biology/Cell Engineering Research Centre, Cancer Biology of State Key Laboratory and State Key Discipline of Cell Biology, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, People’s Republic of China

    Xiao-kui Ma, Yu Li, Hong-bin Zhu, Hao Tang & Zhi-nan Chen

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  1. Li Wang
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Correspondence to Zhi-nan Chen or Ping Zhu.

Additional information

Li Wang and Cong-hua Wang contributed equally to this work.

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Wang, L., Wang, Ch., Jia, Jf. et al. Contribution of Cyclophilin A to the Regulation of Inflammatory Processes in Rheumatoid Arthritis. J Clin Immunol 30, 24–33 (2010). https://doi.org/10.1007/s10875-009-9329-1

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  • DOI: https://doi.org/10.1007/s10875-009-9329-1

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