Digestive Diseases and Sciences

, Volume 62, Issue 6, pp 1511–1517 | Cite as

Serum Cyclophilin A Correlates with Increased Tissue MMP-9 in Patients with Ulcerative Colitis, but Not with Crohn’s Disease

  • Aleksandra Piechota-PolanczykEmail author
  • Marcin Włodarczyk
  • Aleksandra Sobolewska-Włodarczyk
  • Mateusz Jonakowski
  • Andrzej Pilarczyk
  • Krystyna Stec-Michalska
  • Maria Wiśniewska-Jarosińska
  • Jakub Fichna
Original Article



Cyclophilin A (CyPA) is an immunomodulatory protein, high expression of which correlates with poor outcome of patients with inflammatory diseases. However, its role in inflammatory bowel disease (IBD) has not been studied.


This study analyzes the correlation between cyclophilin A, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP (TIMP)/MMP-9 complexes in the inflamed and non-inflamed colon mucosa of UC and CD patients.


Serum and biopsy specimens from inflamed and non-inflamed colonic mucosa of 38 patients with IBD (19 with UC and 19 with CD) and 16 controls were included in our study. We measured serum and tissue level of CyPA, and tissue level of TNF-α, MMP-9, TIMP-1/MMP-9, and TIMP-2/MMP-9 using ELISA method.


Our results indicated that serum, but not tissue CyPA is increased in UC, rather than in CD patients, compared to the control. The increase correlated with higher tissue concentration of MMP-9 and TNF-α, especially in the UC group. Moreover, we observed significantly higher level of TIMP-1/MMP-9 in UC and CD group, which overlapped with the change in MMP-9. There was no change in TIMP-2/MMP-9 in the analyzed groups.


The current study suggests that serum CyPA may be an independent additional marker of IBD, especially of UC. Higher CyPA level may be followed by increased MMP-9 in those patients. However, further studies are necessary to verify the role of CyPA in IBD development.


Crohn’s disease Ulcerative colitis Cyclophilin A Matrix metalloproteinase 9 Tissue inhibitor of metalloproteinase 



Supported by the grants from the Medical University of Lodz (#503/1-156-04/503-01 to JF). Aleksandra Piechota-Polanczyk is currently working at the Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University is a partner of the Leading National Research Center (KNOW) supported by the Ministry of Science and Higher Education.

Compliance with ethical standards

Conflict of interest



  1. 1.
    Matricon J, Barnich N, Ardid D. Immunopathogenesis of inflammatory bowel disease. Self Nonself. 2010;1:299–309.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596–604.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Suzuki J, Jin ZG, Meoli DF, et al. Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells. Circ Res. 2006;98:811–817.CrossRefPubMedGoogle Scholar
  4. 4.
    Nigro P, Pompilio G, Capogrossi MC. Cyclophilin A: a key player for human disease. Cell Death Dis. 2013;4:e888.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wang L, Wang CH, Jia JF, et al. Contribution of cyclophilin A to the regulation of inflammatory processes in rheumatoid arthritis. J Clin Immunol. 2010;30:24–33.CrossRefPubMedGoogle Scholar
  6. 6.
    Li Y, Guo H, Dong D, et al. Expression and prognostic relevance of cyclophilin A and matrix metalloproteinase 9 in esophageal squamous cell carcinoma. Diagn Pathol. 2013;8:207.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Gao Q, Meijer MJ, Kubben FJ, et al. Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases. Dig Liver Dis. 2005;37:584–592.CrossRefPubMedGoogle Scholar
  8. 8.
    Santana A, Medina C, Paz-Cabrera MC, et al. Attenuation of dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient mice. World J Gastroenterol. 2006;12:6464–6472.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    La Pietra V, Marinelli L, Cosconati S, et al. Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization. Eur J Med Chem. 2012;47:143–152.CrossRefPubMedGoogle Scholar
  10. 10.
    Meijer MJ, Mieremet-Ooms MA, van der Zon AM, et al. Increased mucosal matrix metalloproteinase-1, -2, -3 and -9 activity in patients with inflammatory bowel disease and the relation with Crohn’s disease phenotype. Dig Liver Dis. 2007;39:733–739.CrossRefPubMedGoogle Scholar
  11. 11.
    Cadman E, Bostwick JR, Eichberg J. Determination of protein by a modified Lowry procedure in the presence of some commonly used detergents. Anal Biochem. 1979;96:21–23.CrossRefPubMedGoogle Scholar
  12. 12.
    Yuan W, Ge H, He B. Pro-inflammatory activities induced by CyPA–EMMPRIN interaction in monocytes. Atherosclerosis. 2010;213:415–421.CrossRefPubMedGoogle Scholar
  13. 13.
    Heinzmann D, Bangert A, Muller AM, et al. The novel extracellular cyclophilin A (CyPA)—inhibitor MM284 reduces myocardial inflammation and remodeling in a mouse model of troponin I—Induced Myocarditis. PLoS ONE. 2015;10:e0124606.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lakatos G, Hritz I, Varga MZ, et al. The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases. Dig Dis. 2012;30:289–295.CrossRefPubMedGoogle Scholar
  15. 15.
    O’Sullivan S, Gilmer JF, Medina C. Matrix metalloproteinases in inflammatory bowel disease: an update. Mediators Inflamm. 2015;2015:964131.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M. Cyclophilin–CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol. 2010;160:305–317.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Song T, Yang M, Chen J, et al. Prognosis of sepsis induced by cecal ligation and puncture in mice improved by anti-Clonorchis Sinensis cyclopholin a antibodies. Parasit Vectors. 2015;8:502.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dear JW, Leelahavanichkul A, Aponte A, et al. Liver proteomics for therapeutic drug discovery: inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure. Crit Care Med. 2007;35:2319–2328.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhu X, Song Z, Zhang S, et al. CD147: a novel modulator of inflammatory and immune disorders. Curr Med Chem. 2014;21:2138–2145.CrossRefPubMedGoogle Scholar
  20. 20.
    Saksena S, Theegala S, Bansal N, et al. Mechanisms underlying modulation of monocarboxylate transporter 1 (MCT1) by somatostatin in human intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2009;297:G878–G885.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Jin ZG, Lungu AO, Xie L, et al. Cyclophilin A is a proinflammatory cytokine that activates endothelial cells. Arterioscler Thromb Vasc Biol. 2004;24:1186–1191.CrossRefPubMedGoogle Scholar
  22. 22.
    Bahmed K, Henry C, Holliday M, et al. Extracellular cyclophilin-A stimulates ERK1/2 phosphorylation in a cell-dependent manner but broadly stimulates nuclear factor kappa B. Cancer Cell Int. 2012;12:19.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Xie Z, Qu Y, Leng Y, et al. Human colon carcinogenesis is associated with increased interleukin-17-driven inflammatory responses. Drug Des Devel Ther. 2015;9:1679–1689.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Qian Z, Zhao X, Jiang M, et al. Downregulation of cyclophilin A by siRNA diminishes non-small cell lung cancer cell growth and metastasis via the regulation of matrix metallopeptidase 9. BMC Cancer. 2012;12:442.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Manicone AM, McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol. 2008;19:34–41.CrossRefPubMedGoogle Scholar
  26. 26.
    Jakubowska K, Pryczynicz A, Januszewska J, et al. Expressions of matrix metalloproteinases 2, 7, and 9 in carcinogenesis of pancreatic ductal adenocarcinoma. Dis Markers. 2016;2016:9895721.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mao JW, He XM, Tang HY, Wang YD. Protective role of metalloproteinase inhibitor (AE-941) on ulcerative colitis in rats. World J Gastroenterol. 2012;18:7063–7069.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Medina C, Santana A, Paz-Cabrera MC, et al. Increased activity and expression of gelatinases in ischemic colitis. Dig Dis Sci. 2006;51:2393–2399.CrossRefPubMedGoogle Scholar
  29. 29.
    Matusiewicz M, Neubauer K, Mierzchala-Pasierb M, et al. Matrix metalloproteinase-9: its interplay with angiogenic factors in inflammatory bowel diseases. Dis Markers. 2014;2014:643645.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yang Y, Lu N, Zhou J, et al. Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford). 2008;47:1299–1310.CrossRefGoogle Scholar
  31. 31.
    Iordanskaia T, Malesevic M, Fischer G, et al. Targeting extracellular cyclophilins ameliorates disease progression in experimental biliary atresia. Mol Med. 2015;21:657–664.CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Xu Q, Cao X, Pan J, et al. Extracellular matrix metalloproteinase inducer (EMMPRIN) remodels the extracellular matrix through enhancing matrix metalloproteinases (MMPs) and inhibiting tissue inhibitors of MMPs expression in HPV-positive cervical cancer cells. Eur J Gynaecol Oncol. 2015;36:539–545.PubMedGoogle Scholar
  33. 33.
    Calabro SR, Maczurek AE, Morgan AJ, et al. Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis. PLoS ONE. 2014;9:e90571.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Attia M, Huet E, Gossard C, et al. Early events of overused supraspinatus tendons involve matrix metalloproteinases and EMMPRIN/CD147 in the absence of inflammation. Am J Sports Med. 2013;41:908–917.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Aleksandra Piechota-Polanczyk
    • 1
    • 4
    Email author
  • Marcin Włodarczyk
    • 1
    • 3
  • Aleksandra Sobolewska-Włodarczyk
    • 1
    • 2
  • Mateusz Jonakowski
    • 1
  • Andrzej Pilarczyk
    • 1
  • Krystyna Stec-Michalska
    • 2
  • Maria Wiśniewska-Jarosińska
    • 2
  • Jakub Fichna
    • 1
  1. 1.Department of Biochemistry, Faculty of MedicineMedical University of LodzLodzPoland
  2. 2.Department of Gastroenterology, Faculty of Military MedicineMedical University of LodzLodzPoland
  3. 3.Department of General and Colorectal Surgery, Faculty of Military MedicineMedical University of LodzLodzPoland
  4. 4.Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and BiotechnologyJagiellonian UniversityKrakówPoland

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