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. 2004 Jun 1;380(Pt 2):425–433. doi: 10.1042/BJ20031896

Induction of lysosomal and plasma membrane-bound sialidases in human T-cells via T-cell receptor.

Peng Wang 1, Ji Zhang 1, Hong Bian 1, Ping Wu 1, Reshma Kuvelkar 1, Ted T Kung 1, Yvette Crawley 1, Robert W Egan 1, M Motasim Billah 1
PMCID: PMC1224187  PMID: 14992689

Abstract

Among the three isoenzymes of neuraminidase (Neu) or sialidase, Neu-1 has been suggested to be induced by cell activation and to be involved in IL (interleukin)-4 biosynthesis in murine T-cells. In the present study, we found that antigen-induced airway eosinophilia, a typical response dependent on Th2 (T-helper cell type 2) cytokines, as well as mRNA expression of Th2 cytokines, including IL-4, are suppressed in Neu-1-deficient mice, thereby demonstrating the in vivo role of murine Neu-1 in regulation of Th2 cytokines. To elucidate the roles of various sialidases in human T-cell activation, we investigated their tissue distribution, gene induction and function. Neu-1 is the predominant isoenzyme at the mRNA level in most tissues and cells in both mice and humans, including T-cells. T-cells also have significant levels of Neu-3 mRNAs, albeit much lower than those of Neu-1, whereas the levels of Neu-2 mRNAs are minimal. In human T-cells, both Neu-1 and Neu-3 mRNAs are significantly induced by T-cell-receptor stimulation, as is sialidase activity against 4-methylumbelliferyl- N -acetylneuramic acid (a substrate for both Neu-1 and Neu-3) and the ganglioside G(D1a) [NeuAcalpha2-3Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3)Galbeta1-4Glcbeta1-cer] (a substrate for Neu-3, but not for Neu-1). The expression of the two sialidase genes may be under differential regulation. Western blot analysis and enzymic comparison with recombinant sialidases have revealed that Neu-3 is induced as a major isoform in activated cells. The induction of Neu-1 and Neu-3 in T-cells is unique. In human monocytes and neutrophils stimulated with various agents, the only observation of sialidase induction has been by IL-1 in neutrophils. Functionally, a major difference has been observed in Jurkat T-cell lines over-expressing Neu-1- and Neu-3. Upon T-cell receptor stimulation, IL-2, interferon-gamma, IL-4 and IL-13 are induced in the Neu-1 line, whereas in the Neu-3 line the same cytokines are induced, with the exception of IL-4. Taken together, these results suggest an important immunoregulatory role for both Neu-1 and Neu-3 in humans.

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Selected References

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  1. Achyuthan K. E., Achyuthan A. M. Comparative enzymology, biochemistry and pathophysiology of human exo-alpha-sialidases (neuraminidases). Comp Biochem Physiol B Biochem Mol Biol. 2001 May;129(1):29–64. doi: 10.1016/s1096-4959(01)00372-4. [DOI] [PubMed] [Google Scholar]
  2. Arai N., Lee H. J., Ferber I., Kurata H., O'Garra A. Multiple levels of regulation of Th2 cytokine gene expression. Cold Spring Harb Symp Quant Biol. 1999;64:589–598. doi: 10.1101/sqb.1999.64.589. [DOI] [PubMed] [Google Scholar]
  3. Beck J. A., Lloyd S., Hafezparast M., Lennon-Pierce M., Eppig J. T., Festing M. F., Fisher E. M. Genealogies of mouse inbred strains. Nat Genet. 2000 Jan;24(1):23–25. doi: 10.1038/71641. [DOI] [PubMed] [Google Scholar]
  4. Buxton R. C., Edwards B., Juo R. R., Voyta J. C., Tisdale M., Bethell R. C. Development of a sensitive chemiluminescent neuraminidase assay for the determination of influenza virus susceptibility to zanamivir. Anal Biochem. 2000 May 1;280(2):291–300. doi: 10.1006/abio.2000.4517. [DOI] [PubMed] [Google Scholar]
  5. Caldwell Sheila, Heitger Andreas, Shen Weiping, Liu Yihui, Taylor Barbara, Ladisch Stephan. Mechanisms of ganglioside inhibition of APC function. J Immunol. 2003 Aug 15;171(4):1676–1683. doi: 10.4049/jimmunol.171.4.1676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen X. P., Ding X., Daynes R. A. Ganglioside control over IL-4 priming and cytokine production in activated T cells. Cytokine. 2000 Jul;12(7):972–985. doi: 10.1006/cyto.1999.0596. [DOI] [PubMed] [Google Scholar]
  7. Chen X. P., Enioutina E. Y., Daynes R. A. The control of IL-4 gene expression in activated murine T lymphocytes: a novel role for neu-1 sialidase. J Immunol. 1997 Apr 1;158(7):3070–3080. [PubMed] [Google Scholar]
  8. Cross Alan S., Sakarya Serhan, Rifat Salahaldin, Held Thomas K., Drysdale Beth-Ellen, Grange Philippe A., Cassels Frederick J., Wang Lai-Xi, Stamatos Nicholas, Farese Ann. Recruitment of murine neutrophils in vivo through endogenous sialidase activity. J Biol Chem. 2002 Nov 22;278(6):4112–4120. doi: 10.1074/jbc.M207591200. [DOI] [PubMed] [Google Scholar]
  9. Gee Katrina, Kozlowski Maya, Kumar Ashok. Tumor necrosis factor-alpha induces functionally active hyaluronan-adhesive CD44 by activating sialidase through p38 mitogen-activated protein kinase in lipopolysaccharide-stimulated human monocytic cells. J Biol Chem. 2003 Jul 16;278(39):37275–37287. doi: 10.1074/jbc.M302309200. [DOI] [PubMed] [Google Scholar]
  10. Greffard A., Pairon J. C., Terzidis-Trabelsi H., Heslan J. M., Bignon J., Lambre C. R., Pilatte Y. Initial characterization of human thymocyte sialidase activity: evidence that this enzymatic system is not altered during the course of T-cell maturation. Int J Biochem. 1994 Jun;26(6):769–776. doi: 10.1016/0020-711x(94)90106-6. [DOI] [PubMed] [Google Scholar]
  11. Hasegawa T., Yamaguchi K., Wada T., Takeda A., Itoyama Y., Miyagi T. Molecular cloning of mouse ganglioside sialidase and its increased expression in Neuro2a cell differentiation. J Biol Chem. 2000 Mar 17;275(11):8007–8015. doi: 10.1074/jbc.275.11.8007. [DOI] [PubMed] [Google Scholar]
  12. Hata K., Wada T., Hasegawa A., Kiso M., Miyagi T. Purification and characterization of a membrane-associated ganglioside sialidase from bovine brain. J Biochem. 1998 May;123(5):899–905. doi: 10.1093/oxfordjournals.jbchem.a022022. [DOI] [PubMed] [Google Scholar]
  13. Hybertson B. M., Jepson E. K., Cho O. J., Clarke J. H., Lee Y. M., Repine J. E. TNF mediates lung leak, but not neutrophil accumulation, in lungs of rats given IL-1 intratracheally. Am J Respir Crit Care Med. 1997 Jun;155(6):1972–1976. doi: 10.1164/ajrccm.155.6.9196104. [DOI] [PubMed] [Google Scholar]
  14. Igdoura S. A., Mertineit C., Trasler J. M., Gravel R. A. Sialidase-mediated depletion of GM2 ganglioside in Tay-Sachs neuroglia cells. Hum Mol Genet. 1999 Jun;8(6):1111–1116. doi: 10.1093/hmg/8.6.1111. [DOI] [PubMed] [Google Scholar]
  15. Irani D. N., Lin K. I., Griffin D. E. Brain-derived gangliosides regulate the cytokine production and proliferation of activated T cells. J Immunol. 1996 Nov 15;157(10):4333–4340. [PubMed] [Google Scholar]
  16. Johansson A. C., Vestberg M., Holmdahl R. Non-major histocompatibility complex dependent variations in lymphocyte activity between inbred mouse strains susceptible to various autoimmune diseases. Scand J Immunol. 2000 Jul;52(1):21–29. doi: 10.1046/j.1365-3083.2000.00738.x. [DOI] [PubMed] [Google Scholar]
  17. Kanda N., Watanabe S. Gangliosides GD1b, GT1b, and GQ1b enhance IL-2 and IFN-gamma production and suppress IL-4 and IL-5 production in phytohemagglutinin-stimulated human T cells. J Immunol. 2001 Jan 1;166(1):72–80. doi: 10.4049/jimmunol.166.1.72. [DOI] [PubMed] [Google Scholar]
  18. Katoh S., Miyagi T., Taniguchi H., Matsubara Y., Kadota J., Tominaga A., Kincade P. W., Matsukura S., Kohno S. Cutting edge: an inducible sialidase regulates the hyaluronic acid binding ability of CD44-bearing human monocytes. J Immunol. 1999 May 1;162(9):5058–5061. [PubMed] [Google Scholar]
  19. Kopitz J., Sinz K., Brossmer R., Cantz M. Partial characterization and enrichment of a membrane-bound sialidase specific for gangliosides from human brain tissue. Eur J Biochem. 1997 Sep 1;248(2):527–534. doi: 10.1111/j.1432-1033.1997.00527.x. [DOI] [PubMed] [Google Scholar]
  20. Kung T. T., Jones H., Adams G. K., 3rd, Umland S. P., Kreutner W., Egan R. W., Chapman R. W., Watnick A. S. Characterization of a murine model of allergic pulmonary inflammation. Int Arch Allergy Immunol. 1994 Sep;105(1):83–90. doi: 10.1159/000236807. [DOI] [PubMed] [Google Scholar]
  21. Landolfi N. F., Leone J., Womack J. E., Cook R. G. Activation of T lymphocytes results in an increase in H-2-encoded neuraminidase. Immunogenetics. 1985;22(2):159–167. doi: 10.1007/BF00563513. [DOI] [PubMed] [Google Scholar]
  22. Lieser M., Harms E., Kern H., Bach G., Cantz M. Ganglioside GM3 sialidase activity in fibroblasts of normal individuals and of patients with sialidosis and mucolipidosis IV. Subcellular distribution and and some properties. Biochem J. 1989 May 15;260(1):69–74. doi: 10.1042/bj2600069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lin Tong-Jun, Garduno Rafael, Boudreau Robert T. M., Issekutz Andrew C. Pseudomonas aeruginosa activates human mast cells to induce neutrophil transendothelial migration via mast cell-derived IL-1 alpha and beta. J Immunol. 2002 Oct 15;169(8):4522–4530. doi: 10.4049/jimmunol.169.8.4522. [DOI] [PubMed] [Google Scholar]
  24. Lukong K. E., Seyrantepe V., Landry K., Trudel S., Ahmad A., Gahl W. A., Lefrancois S., Morales C. R., Pshezhetsky A. V. Intracellular distribution of lysosomal sialidase is controlled by the internalization signal in its cytoplasmic tail. J Biol Chem. 2001 Sep 24;276(49):46172–46181. doi: 10.1074/jbc.M104547200. [DOI] [PubMed] [Google Scholar]
  25. Milner C. M., Smith S. V., Carrillo M. B., Taylor G. L., Hollinshead M., Campbell R. D. Identification of a sialidase encoded in the human major histocompatibility complex. J Biol Chem. 1997 Feb 14;272(7):4549–4558. doi: 10.1074/jbc.272.7.4549. [DOI] [PubMed] [Google Scholar]
  26. Miyagi T., Sagawa J., Konno K., Handa S., Tsuiki S. Biochemical and immunological studies on two distinct ganglioside-hydrolyzing sialidases from the particulate fraction of rat brain. J Biochem. 1990 May;107(5):787–793. doi: 10.1093/oxfordjournals.jbchem.a123126. [DOI] [PubMed] [Google Scholar]
  27. Miyagi T., Tsuiki S. Purification and characterization of cytosolic sialidase from rat liver. J Biol Chem. 1985 Jun 10;260(11):6710–6716. [PubMed] [Google Scholar]
  28. Miyagi T., Wada T., Iwamatsu A., Hata K., Yoshikawa Y., Tokuyama S., Sawada M. Molecular cloning and characterization of a plasma membrane-associated sialidase specific for gangliosides. J Biol Chem. 1999 Feb 19;274(8):5004–5011. doi: 10.1074/jbc.274.8.5004. [DOI] [PubMed] [Google Scholar]
  29. Monti E., Preti A., Rossi E., Ballabio A., Borsani G. Cloning and characterization of NEU2, a human gene homologous to rodent soluble sialidases. Genomics. 1999 Apr 1;57(1):137–143. doi: 10.1006/geno.1999.5749. [DOI] [PubMed] [Google Scholar]
  30. Monti Eugenio, Preti Augusto, Venerando Bruno, Borsani Giuseppe. Recent development in mammalian sialidase molecular biology. Neurochem Res. 2002 Aug;27(7-8):649–663. doi: 10.1023/a:1020276000901. [DOI] [PubMed] [Google Scholar]
  31. Naraparaju V. R., Yamamoto N. Roles of beta-galactosidase of B lymphocytes and sialidase of T lymphocytes in inflammation-primed activation of macrophages. Immunol Lett. 1994 Dec;43(3):143–148. doi: 10.1016/0165-2478(94)90214-3. [DOI] [PubMed] [Google Scholar]
  32. Oh S., Eichelberger M. C. Polarization of allogeneic T-cell responses by influenza virus-infected dendritic cells. J Virol. 2000 Sep;74(17):7738–7744. doi: 10.1128/jvi.74.17.7738-7744.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Oh S., Eichelberger M. C. Polarization of allogeneic T-cell responses by influenza virus-infected dendritic cells. J Virol. 2000 Sep;74(17):7738–7744. doi: 10.1128/jvi.74.17.7738-7744.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schauer R. Achievements and challenges of sialic acid research. Glycoconj J. 2000 Jul-Sep;17(7-9):485–499. doi: 10.1023/A:1011062223612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shen Weiping, Ladisch Stephan. Ganglioside GD1a impedes lipopolysaccharide-induced maturation of human dendritic cells. Cell Immunol. 2002 Dec;220(2):125–133. doi: 10.1016/s0008-8749(03)00004-2. [DOI] [PubMed] [Google Scholar]
  36. Taira S., Nariuchi H. Possible role of neuraminidase in activated T cells in the recognition of allogeneic Ia. J Immunol. 1988 Jul 15;141(2):440–446. [PubMed] [Google Scholar]
  37. Traving C., Schauer R. Structure, function and metabolism of sialic acids. Cell Mol Life Sci. 1998 Dec;54(12):1330–1349. doi: 10.1007/s000180050258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. WARREN L. The thiobarbituric acid assay of sialic acids. J Biol Chem. 1959 Aug;234(8):1971–1975. [PubMed] [Google Scholar]
  39. Wada T., Yoshikawa Y., Tokuyama S., Kuwabara M., Akita H., Miyagi T. Cloning, expression, and chromosomal mapping of a human ganglioside sialidase. Biochem Biophys Res Commun. 1999 Jul 22;261(1):21–27. doi: 10.1006/bbrc.1999.0973. [DOI] [PubMed] [Google Scholar]
  40. Wang P., Myers J. G., Wu P., Cheewatrakoolpong B., Egan R. W., Billah M. M. Expression, purification, and characterization of human cAMP-specific phosphodiesterase (PDE4) subtypes A, B, C, and D. Biochem Biophys Res Commun. 1997 May 19;234(2):320–324. doi: 10.1006/bbrc.1997.6636. [DOI] [PubMed] [Google Scholar]
  41. Wang P., Wu P., Egan R. W., Billah M. M. Human phosphodiesterase 8A splice variants: cloning, gene organization, and tissue distribution. Gene. 2001 Dec 12;280(1-2):183–194. doi: 10.1016/s0378-1119(01)00783-1. [DOI] [PubMed] [Google Scholar]
  42. Wang P., Wu P., Ohleth K. M., Egan R. W., Billah M. M. Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils. Mol Pharmacol. 1999 Jul;56(1):170–174. doi: 10.1124/mol.56.1.170. [DOI] [PubMed] [Google Scholar]
  43. Warner T. G., Chang J., Ferrari J., Harris R., McNerney T., Bennett G., Burnier J., Sliwkowski M. B. Isolation and properties of a soluble sialidase from the culture fluid of Chinese hamster ovary cells. Glycobiology. 1993 Oct;3(5):455–463. doi: 10.1093/glycob/3.5.455. [DOI] [PubMed] [Google Scholar]
  44. Womack J. E., Yan D. L., Potier M. Gene for neuraminidase activity on mouse chromosome 17 near h-2: pleiotropic effects on multiple hydrolases. Science. 1981 Apr 3;212(4490):63–65. doi: 10.1126/science.7209520. [DOI] [PubMed] [Google Scholar]
  45. Zhang J., Kuvelkar R., Murgolo N. J., Taremi S. S., Chou C. C., Wang P., Billah M. M., Egan R. W. Mapping and characterization of the epitope(s) of Sch 55700, a humanized mAb, that inhibits human IL-5. Int Immunol. 1999 Dec;11(12):1935–1944. doi: 10.1093/intimm/11.12.1935. [DOI] [PubMed] [Google Scholar]

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