Comparison of YKL-39 and CHIT-1 expression during macrophages differentiation and polarization


The chitinase-like proteins YKL-39 (chitinase 3-like-2) and Chitortriosidase (CHIT-1) are members of the chitinases family. YKL-39 expression has been associated with osteoarthritis, whereas CHIT-1 activity is regarded as a biochemical marker of macrophage activation. So far, the physiological or pathological role of YKL-39 in the inflammation is still poorly understood. We compared YKL-39 and CHIT-1 modulation during monocyte to macrophage transition and polarization. Gene expression analysis was investigated by real-time PCR from mRNA of human monocytes obtained from buffy coat of healthy volunteers, from mRNA of polarized macrophages to classically activated macrophages (or M1), obtained by interferon-γ and lipopolysaccharide exposure, and from mRNA of alternatively activated macrophages (or M2) obtained by interleukin-4 exposure. We demonstrated different variations of YKL-39 and CHIT-1 production during macrophages polarization. CHIT-1 levels gradually increase in the course of the time with a peak of expression between the fifth and the seventh day of culture. In contrast, YKL-39 expression was unaltered in the diverse stage of HMMs differentiation, but increased significantly in M1 polarized macrophages and reverted to base levels in M2 polarized macrophages. These findings indicated that the function of YKL-39 is much more restricted and selective than that exerted by CHIT-1.

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Rosa, M. , Tibullo, D. , Malaguarnera, M. , Tuttobene, M. and Malaguarnera, L. (2013) Comparison of YKL-39 and CHIT-1 expression during macrophages differentiation and polarization. Modern Research in Inflammation, 2, 82-89. doi: 10.4236/mri.2013.24011.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Funkhouser, J.D. and Aronson Jr., N.N. (2007) Chitinase family GH18: Evolutionary insights from the genomic history of a diverse protein family. BMC Evolutionary Biology, 7, 96. 10.1186/1471-2148-7-96
[2] Schimpl, M., Rush, C.L., Betou, M., Eggleston, I.M., Recklies, A.D. and van Aalten, DM. (2012) Human YKL-39 is a pseudo-chitinase with retained chito-oligosaccharide-binding properties. Biochemical Journal, 446, 149-157.
[3] Hu, B., Trinh, K., Figueiira, W.F. and Price, P. (1996) Isolation and sequence of a novel human chondrocyte protein related to mammalian members of the chitinase protein family. The Journal of Biological Chemistry, 271, 19415-19420.
[4] Steck, E., Breit, S., Breusch, S.J. Axt, M. and Richter, W. (2002) Enhanced expression of the human chitinase 3-like 2 gene (YKL-39) but not chitinase 3-like 1 gene (YKL-40) in osteoarthritic cartilage. Biochemical and Biophysical Research Communications, 299, 109-115. S0006-291X(02)02585-8
[5] Knorr, T., Obermayr, F., Bartnik, E., Zien, A. and Aigner, T. (2003) YKL-39 (chitinase 3-like protein 2), but not YKL-40 (chitinase 3-like protein 1), is up regulated in osteoarthritic chondrocytes. Annals of the Rheumatic Diseases, 62, 995-998.
[6] De Ceuninck, F., Marcheteau, E., Berger, S., Caliez, A., Dumont, V., Raes, M., Anract, P., Leclerc, G, Boutin, J.A. and Ferry, G. (2005) Assessment of some tools for the characterization of the human osteoarthritic cartilage proteome. Journal of Biomolecular Techniques, 16, 256-265.
[7] Du, H., Masuko-Hongo, K., Nakamura, H., Xiang, Y., Bao, C.D., Wang, X.D., Chen, S.L., Nishioka, K. and Kato, T. (2005) The prevalence of autoantibodies against cartilage intermediate layer protein, YKL-39, osteopontin, and cyclic citrullinated peptide in patients with earlystage knee osteoarthritis: Evidence of a variety of autoimmune processes. Rheumatology International, 26, 35-41.
[8] Tsuruha, J., Masuko-Hongo, K., Kato, T., Sakata, M., Nakamura, H., Sekine, T., Takigawa, M. and Nishioka, K. (2002) Autoimmunity against YKL-39, a human cartilage derived protein, in patients with osteoarthritis. Journal of Rheumatology, 29, 1459-1466.
[9] Kzhyshkowska, J., Gratchev, A. and Goerdt, S. (2007) Human chitinases and chitinase-like proteins as indicators for inflammation and cancer. Journal of Biomarker Insights, 2, 128-146.
[10] Boot, R.G., van Achterberg, T.A., van Aken, B.E., Renkema, G.H., Jacobs, M.J., Aerts, J.M. and de Vries, C.J. (1999) Strong induction of members of the chitinase family of proteins in atherosclerosis: Chitotriosidase and human cartilage gp-39 expressed in lesion macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology, 19, 687-694.
[11] Malaguarnera, L. (2006) Chitotriosidase: The yin and yang. Cellular and Molecular Life Sciences, 63, 3018-3029.
[12] Hall, A.J., Morroll, S., Tighe, P., G?tz, F. and Falcone, F.H. (2008) Human chitotriosidase is expressed in the eye and lacrimal gland and has an antimicrobial spectrum different from lysozyme. Microbes and Infection, 10, 69-78.
[13] Boven, L.A., van Meurs, M., Boot, R.G., Mehta, A., Boon, L., Aerts, J.M. and Laman, J.D. (2004) Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. American Journal of Clinical Pathology, 122, 359-369. BG5VA8JRDQH1M7HN
[14] Aerts, J.M., Hollak, C.E., van Breemen, M., Maas, M., Groener, J.E. and Boot, R.G. (2005) Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases. Acta Paediatrica Supplement, 94, 43-46.
[15] Brinkman, J., Wijburg, F.A., Hollak, C.E., Groener, J.E., Verhoek, M., Scheij, S., Scheij, S., Aten, J., Boot, R.G. and Aerts, J.M. (2005) Plasma chitotriosidase and CCL18: Early biochemical surrogate markers in type B Niemann-Pick disease. Journal of Inherited Metabolic Disease, 28, 13-20. 10.1007/s10545-005-4416-9
[16] Barone, R., Malaguarnera, L., Angius, A. and Musumeci, S. (2003) Plasma chitotriosidase activity in patients with beta-thalassemia. American Journal of Hematology, 72, 285-286. 10.1002/ajh.10294
[17] Bargagli, E., Bennett, D., Maggiorelli, C., Di Sipio, P., Margollicci, M., Bianchi, N. and Rottoli, P. (2013) Human chitotriosidase: A sensitive biomarker of sarcoidosis. Journal of Clinical Immunology, 33, 264-270.
[18] Comabella, M., Domínguez, C., Rio, J., Martín-Gallán, P., Vilches, A., Vilarrasa, N., Espejo, C. and Montalban, X. (2009) Plasma chitotriosidase activity in multiple sclerosis. Clinical Immunology, 131, 216-222.
[19] Malaguarnera, L., Simporè, J., Prodi, D.A., Angius, A., Sassu, A., Persico, I., Barone, R. and Musumeci, S. (2003) 24-bp duplication in exon 10 of human chitotriosidase gene from the sub-Saharan to the Mediterranean area: Role of parasitic diseases and environmental conditions. Genes and Immunity, 4, 570-574.
[20] Malaguarnera, L., Di Rosa, M., Zambito, A.M., Dell’Ombra, N., Di Marco, R. and Malaguarnera, M. (2006) Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution. American Journal of Gastroenterology, 101, 2060-2069.
[21] Malaguarnera, L., Di Rosa, M., Zambito, A.M., Dell’Ombra, N., Nicoletti, F. and Malaguarnera, M. (2006) Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut, 55, 1313-1320.
[22] Artieda, M., Cenarro, A., Ganán, A., Lukic, A., Moreno, E., Puzo, J., Pocoví, M. and Civeira, F. (2007) Serum chitotriosidase activity, a marker of activated macrophages, predicts new cardiovascular events independently of Creactive protein. Cardiology, 108, 297-306. 000099099
[23] Palasik, W., Fiszer, U., Lechowicz, W., Czartoryska, B., Krzesiewicz, M. and Lugowska, A. (2005) Assessment of relations between clinical outcome of ischemic stroke and activity of inflammatory processes in the acute phase based on examination of selected parameters. European Neurology, 53, 188-193.
[24] Di Rosa, M., Dell’Ombra, N., Zambito, A.M., Malaguarnera, M., Nicoletti, F. and Malaguarnera, L. (2006) Chitotriosidase and inflammatory mediator levels in Alzheimer’s disease and cerebrovascular dementia. European Journal of Neuroscience, 23, 2648-2656.
[25] Kzhyshkowska, J., Mamidi, S., Gratchev, A., Kremmer, E., Schmuttermaier, C., Krusell, L., Haus, G., Utikal, J., Schledzewski, K., Scholtze, J. and Goerdt, S. (2006) Novel stabilin-1 interacting chitinase-like protein (SICLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood, 107, 3221-3228.
[26] Ross, R., Ross, X.L., Ghadially, H., Lahr, T., Schwing, J., Knop, J. and Reske-Kunz, AB. (1999) Mouse langerhans cells differentially express an activated T cell attracting CC chemokine. Journal of Investigative Dermatology, 113, 991-998.
[27] Martinez, F.O., Sica, A. and Mantovani, A.M. (2008) Macrophage activation and polarization. Frontiers in Bioscience, 13, 453-461.
[28] Gratchev, A., Schmuttermaier, C., Mamidi, S., Gooi, L., Goerdt, S. and Kzhyshkowska, J. (2008) Expression of osteoarthritis marker YKL-39 is stimulated by transforming growth factor beta (TGF-beta) and IL-4 in differentiating macrophages. Journal of Biomarker Insights, 3, 39-44.
[29] Malaguarnera, L., Imbesi, R., Di Rosa, M., Scuto, A., Castrogiovanni, P., Messina, A. and Sanfilippo, S. (2005) Action of prolactin, IFN-gamma, TNF-alpha and LPS on heme oxygenase-1 expression and VEGF release in human monocytes/macrophages. International Immunopharmacology, 5, 1458-1469.
[30] Fagone, P., Di Rosa, M., Palumbo, M., De Gregorio, C., Nicoletti, F. and Malaguarnera, L. (2012) Modulation of heat shock proteins during macrophage differentiation. Inflammation Research, 61, 1131-1139.
[31] Quandt, K., Frech, K., Karas, H., Wingender, E. and Werner, T. (1995) MatInd and MatInspector: New fast and versatile tools for detection of consensus. Matches in nucleotide sequence data. Nucleic Acids Research, 23, 4878-4884.
[32] Heinemeyer, T., Chen, X., Karas, H., Kel, A.E., Kel, O.V., Liebich, I., Meinhardt, T., Reuter, I., Schacherer, F. and Wingender, E. (1999) Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms. Nucleic Acids Research, 27, 318-322.
[33] Klingenhoff, A., Frech, K., Quandt, K. and Werner, T. (1999) Functional promoter modules can be detected by formal models independent of overall nucleotide sequence similarity. Bioinformatics, 15, 180-186.
[34] Frech, K., Danescu-Mayer, J. and Werner, T. (1997) A novel method to develop highly specific models for regulatory units detects a new LTR in GenBank which contains a functional promoter. Journal of Molecular Biology, 270, 674-687.
[35] Di Rosa, M., Malaguarnera, G., De Gregorio, C., D’Amico, F., Mazzarino, M.C. and Malaguarnera, L. (2013) Modulation of chitotriosidase during macrophage differentiation. Cell Biochemistry and Biophysics, 66, 239-247.
[36] Lavorgna, G., Boncinelli, E., Wagner, A. and Werner, T. (1998) Detection of potential target genes in silico? Trends in Genetics, 14, 375-376.
[37] Di Rosa, M., Malaguarnera, G., De Gregorio, C., Drago, F. and Malaguarnera, L. (2013) Evaluation of CHIT3L-1 and CHIT-1 expression in differentiated and polarized macrophages. Inflammation, 36, 482-492.
[38] Ishii, H., Tanaka, H., Katoh, K., Nakamura, H., Nagashima, M. and Yoshino, S. (2002) Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis Cartilage, 10, 277-281.
[39] Malaguarnera, L., Ohazuruike, L.N., Tsianaka, C., Antic, T., Di Rosa, M. and Malaguarnera, M. (2010) Human chitotriosidase polymorphism is associated with human longevity in Mediterranean nonagenarians and centenarians. Journal of Human Genetics, 55, 8-12. 10.1038/jhg.2009.111
[40] Di Rosa, M., Mangano, K., De Gregorio, C., Nicoletti, F. and Malaguarnera, L. (2013) Association of chitotriosidase genotype with the development of nonalcoholic fatty liver disease. Hepatology Research, 43, 267-275.

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