Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter July 20, 2006

Extracellular granzymes: current perspectives

Marguerite S. Buzza and Phillip I. Bird
From the journal


Granzyme A (GrA) and granzyme B (GrB) play key roles in the induction of target cell death induced by cytotoxic lymphocytes. Whilst these roles have been extensively studied, it is becoming apparent that both granzymes also possess extracellular activities. Soluble granzymes are found extracellularly in normal plasma and are elevated in a number of diseases, ranging from viral and bacterial infections to autoimmune diseases. Here, we discuss the current knowledge of extracellular granzyme substrates, inhibitors and functions; and the pathological consequences of extracellular granzymes in disease. In addition, we provide new evidence for the role of glycosaminoglycan-binding sites of granzymes in extracellular matrix remodeling.


Corresponding author


Accardo-Palumbo, A., Ferrante, A., Cadelo, M., Ciccia, F., Parrinello, G., Lipari, L., Giardina, A.R., Riili, M., Giardina, E., Dieli, F., and Triolo, G. (2004). The level of soluble granzyme A is elevated in the plasma and in the Vg9/Vd2 T cell culture supernatants of patients with active Behcet's disease. Clin. Exp. Rheumatol.22, S45–S49.Search in Google Scholar

Augustin, M.T., Kokkonen, J., Karttunen, R., and Karttunen, T.J. (2005). Serum granzymes and CD30 are increased in children's milk protein sensitive enteropathy and celiac disease. J. Allergy Clin. Immunol.115, 157–162.10.1016/j.jaci.2004.10.009Search in Google Scholar

Bade, B., Lohrmann, J., ten Brinke, A., Wolbink, A.M., Wolbink, G.J., ten Berge, I.J., Virchow, J.C. Jr., Luttmann, W., and Hack, C.E. (2005). Detection of soluble human granzyme K in vitro and in vivo. Eur. J. Immunol.35, 2940–2948.10.1002/eji.200526249Search in Google Scholar

Barilla, M.L. and Carsons, S.E. (2000). Fibronectin fragments and their role in inflammatory arthritis. Semin. Arthritis Rheum.29, 252–265.10.1016/S0049-0172(00)80012-8Search in Google Scholar

Baslund, B., Petersen, J., Permin, H., Wiik, A., and Wieslander, J. (1994). Measurements of proteinase 3 and its complexes with α1-proteinase inhibitor and anti-neutrophil cytoplasm antibodies (ANCA) in plasma. J. Immunol. Methods175, 215–225.10.1016/0022-1759(94)90364-6Search in Google Scholar

Bennett, M.R. and Boyle, J.J. (1998). Apoptosis of vascular smooth muscle cells in atherosclerosis. Atherosclerosis138, 3–9.10.1016/S0021-9150(98)00013-6Search in Google Scholar

Bird, C.H., Blink, E.J., Hirst, C.E., Buzza, M.S., Steele, P.M., Sun, J., Jans, D.A., and Bird, P.I. (2001). Nucleocytoplasmic distribution of the ovalbumin serpin PI-9 requires a nonconventional nuclear import pathway and the export factor Crm1. Mol. Cell. Biol.21, 5396–5407.10.1128/MCB.21.16.5396-5407.2001Search in Google Scholar PubMed PubMed Central

Bird, C.H., Sun, J., Ung, K., Karambalis, D., Whisstock, J.C., Trapani, J.A., and Bird, P.I. (2005). Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells. Mol. Cell. Biol.25, 7854–7867.10.1128/MCB.25.17.7854-7867.2005Search in Google Scholar PubMed PubMed Central

Bladergroen, B.A., Strik, M.C., Bovenschen, N., van Berkum, O., Scheffer, G.L., Meijer, C.J., Hack, C.E., and Kummer, J.A. (2001). The granzyme B inhibitor, protease inhibitor 9, is mainly expressed by dendritic cells and at immune-privileged sites. J. Immunol.166, 3218–3225.10.4049/jimmunol.166.5.3218Search in Google Scholar PubMed

Brass, L.F. (2003). Thrombin and platelet activation. Chest124, 18S–25S.10.1378/chest.124.3_suppl.18SSearch in Google Scholar

Bratke, K., Bottcher, B., Leeder, K., Schmidt, S., Kupper, M., Virchow, J.C. Jr., and Luttmann, W. (2004). Increase in granzyme B lymphocytes and soluble granzyme B in bronchoalveolar lavage of allergen challenged patients with atopic asthma. Clin. Exp. Immunol.136, 542–548.10.1111/j.1365-2249.2004.02468.xSearch in Google Scholar PubMed PubMed Central

Brown, G.R., McGuire, M.J., and Thiele, D.L. (1993). Dipeptidyl peptidase I is enriched in granules of in vitro- and in vivo-activated cytotoxic T lymphocytes. J. Immunol.150, 4733–4742.Search in Google Scholar

Browne, K.A., Blink, E., Sutton, V.R., Froelich, C.J., Jans, D.A., and Trapani, J.A. (1999). Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol. Cell. Biol.19, 8604–8615.10.1128/MCB.19.12.8604Search in Google Scholar

Brunner, G., Simon, M.M., and Kramer, M.D. (1990). Activation of pro-urokinase by the human T cell-associated serine proteinase HuTSP-1. FEBS Lett.260, 141–144.10.1016/0014-5793(90)80087-YSearch in Google Scholar

Buzza, M.S., Hirst, C.E., Bird, C.H., Hosking, P., McKendrick, J., and Bird, P.I. (2001). The granzyme B inhibitor, PI-9, is present in endothelial and mesothelial cells, suggesting that it protects bystander cells during immune responses. Cell. Immunol.210, 21–29.10.1006/cimm.2001.1806Search in Google Scholar

Buzza, M.S., Zamurs, L., Sun, J., Bird, C.H., Smith, A.I., Trapani, J.A., Froelich, C.J., Nice, E.C., and Bird, P.I. (2005). Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. J. Biol. Chem.280, 23549–23558.10.1074/jbc.M412001200Search in Google Scholar

Cao, L. and Yang, B.B. (1999). Chondrocyte apoptosis induced by aggrecan G1 domain as a result of decreased cell adhesion. Exp. Cell Res.246, 527–537.10.1006/excr.1998.4335Search in Google Scholar

Choy, J.C., Granville, D.J., Hunt, D.W., and McManus, B.M. (2001). Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J. Mol. Cell. Cardiol.33, 1673–1690.10.1006/jmcc.2001.1419Search in Google Scholar

Choy, J.C., McDonald, P.C., Suarez, A.C., Hung, V.H., Wilson, J.E., McManus, B.M., and Granville, D.J. (2003). Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity. Mod. Pathol.16, 460–470.10.1097/01.MP.0000067424.12280.BCSearch in Google Scholar

Choy, J.C., Hung, V.H., Hunter, A.L., Cheung, P.K., Motyka, B., Goping, I.S., Sawchuk, T., Bleackley, R.C., Podor, T.J., McManus, B.M., and Granville, D.J. (2004). Granzyme B induces smooth muscle cell apoptosis in the absence of perforin: involvement of extracellular matrix degradation. Arterioscler. Thromb. Vasc. Biol.24, 2245–2250.10.1161/01.ATV.0000147162.51930.b7Search in Google Scholar

Clayberger, C. and Krensky, A.M. (2003). Granulysin. Curr. Opin. Immunol.15, 560–565.10.1016/S0952-7915(03)00097-9Search in Google Scholar

Doucey, M.A., Legler, D.F., Faroudi, M., Boucheron, N., Baumgaertner, P., Naeher, D., Cebecauer, M., Hudrisier, D., Ruegg, C., Palmer, E., et al. (2003). The β1 and β3 integrins promote T cell receptor-mediated cytotoxic T lymphocyte activation. J. Biol. Chem.278, 26983–26991.10.1074/jbc.M302709200Search in Google Scholar PubMed

Erickson, H.P. and Carrell, N.A. (1983). Fibronectin in extended and compact conformations. Electron microscopy and sedimentation analysis. J. Biol. Chem.258, 14539–14544.Search in Google Scholar

Froelich, C.J., Zhang, X., Turbov, J., Hudig, D., Winkler, U., and Hanna, W.L. (1993). Human granzyme B degrades aggrecan proteoglycan in matrix synthesized by chondrocytes. J. Immunol.151, 7161–7171.Search in Google Scholar

Froelich, C.J., Orth, K., Turbov, J., Seth, P., Gottlieb, R., Babior, B., Shah, G.M., Bleackley, R.C., Dixit, V.M., and Hanna, W. (1996). New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis. J. Biol. Chem.271, 29073–29079.10.1074/jbc.271.46.29073Search in Google Scholar PubMed

Gahring, L., Carlson, N.G., Meyer, E.L., and Rogers, S.W. (2001). Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation. J. Immunol.166, 1433–1438.10.4049/jimmunol.166.3.1433Search in Google Scholar PubMed

Galvin, J.P., Spaeny-Dekking, L.H., Wang, B., Seth, P., Hack, C.E., and Froelich, C.J. (1999). Apoptosis induced by granzyme B-glycosaminoglycan complexes: implications for granule-mediated apoptosis in vivo. J. Immunol.162, 5345–5350.Search in Google Scholar

Gettins, P.G. (2002). Serpin structure, mechanism, and function. Chem. Rev.102, 4751–4804.10.1021/cr010170+Search in Google Scholar PubMed

Griffiths, G.M. and Isaaz, S. (1993). Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. J. Cell Biol.120, 885–896.10.1083/jcb.120.4.885Search in Google Scholar PubMed PubMed Central

Griffiths, G.M., Alpert, S., Lambert, E., McGuire, J., and Weissman, I.L. (1992). Perforin and granzyme A expression identifying cytolytic lymphocytes in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA89, 549–553.10.1073/pnas.89.2.549Search in Google Scholar PubMed PubMed Central

Grossmann, J. (2002). Molecular mechanisms of ‘detachment-induced apoptosis – Anoikis’. Apoptosis7, 247–260.10.1023/A:1015312119693Search in Google Scholar

Hansen, K.K., Sherman, P.M., Cellars, L., Andrade-Gordon, P., Pan, Z., Baruch, A., Wallace, J.L., Hollenberg, M.D., and Vergnolle, N. (2005). A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis. Proc. Natl. Acad. Sci. USA102, 8363–8368.10.1073/pnas.0409535102Search in Google Scholar PubMed PubMed Central

Held, W., MacDonald, R., and Mueller, C. (1990). Expression of genes encoding cytotoxic cell-associated serine proteases in thymocytes. Int. Immunol.2, 57–62.10.1093/intimm/2.1.57Search in Google Scholar PubMed

Hermsen, C.C., Konijnenberg, Y., Mulder, L., Loe, C., van Deuren, M., van der Meer, J.W., van Mierlo, G.J., Eling, W.M., Hack, C.E., and Sauerwein, R.W. (2003). Circulating concentrations of soluble granzyme A and B increase during natural and experimental Plasmodium falciparum infections. Clin. Exp. Immunol.132, 467–472.10.1046/j.1365-2249.2003.02160.xSearch in Google Scholar PubMed PubMed Central

Hirst, C.E., Buzza, M.S., Sutton, V.R., Trapani, J.A., Loveland, K.L., and Bird, P.I. (2001). Perforin-independent expression of granzyme B and proteinase inhibitor 9 in human testis and placenta suggests a role for granzyme B-mediated proteolysis in reproduction. Mol. Hum. Reprod.7, 1133–1142.10.1093/molehr/7.12.1133Search in Google Scholar PubMed

Hollenberg, M.D. (2003). Proteinase-mediated signaling: proteinase-activated receptors (PARs) and much more. Life Sci.74, 237–246.10.1016/j.lfs.2003.09.010Search in Google Scholar

Hu, S.X., Wang, S., Wang, J.P., Mills, G.B., Zhou, Y., and Xu, H.J. (2003). Expression of endogenous granzyme B in a subset of human primary breast carcinomas. Br. J. Cancer89, 135–139.10.1038/sj.bjc.6601051Search in Google Scholar

Isaaz, S., Baetz, K., Olsen, K., Podack, E., and Griffiths, G.M. (1995). Serial killing by cytotoxic T lymphocytes: T cell receptor triggers degranulation, re-filling of the lytic granules and secretion of lytic proteins via a non-granule pathway. Eur. J. Immunol.25, 1071–1079.10.1002/eji.1830250432Search in Google Scholar

Kahaleh, M.B. and Fan, P.S. (1997). Mechanism of serum-mediated endothelial injury in scleroderma: identification of a granular enzyme in scleroderma skin and sera. Clin. Immunol. Immunopathol.83, 32–40.10.1006/clin.1996.4322Search in Google Scholar

Keefe, D., Shi, L., Feske, S., Massol, R., Navarro, F., Kirchhausen, T., and Lieberman, J. (2005). Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity23, 249–262.10.1016/j.immuni.2005.08.001Search in Google Scholar

Kraan, M.C., Haringman, J.J., Weedon, H., Barg, E.C., Smith, M.D., Ahern, M.J., Smeets, T.J., Breedveld, F.C., and Tak, P.P. (2004). T cells, fibroblast-like synoviocytes, and granzyme B+ cytotoxic cells are associated with joint damage in patients with recent onset rheumatoid arthritis. Ann. Rheum. Dis.63, 483–488.10.1136/ard.2003.009225Search in Google Scholar

Kramer, M.D. and Simon, M.M. (1987). Are proteinases functional molecules of T lymphocytes? Immunol. Today8, 140–142.Search in Google Scholar

Kummer, J.A., Tak, P.P., Brinkman, B.M., van Tilborg, A.A., Kamp, A.M., Verweij, C.L., Daha, M.R., Meinders, A.E., Hack, C.E., and Breedveld, F.C. (1994). Expression of granzymes A and B in synovial tissue from patients with rheumatoid arthritis and osteoarthritis. Clin. Immunol. Immunopathol.73, 88–95.10.1006/clin.1994.1173Search in Google Scholar

Kurschus, F.C., Kleinschmidt, M., Fellows, E., Dornmair, K., Rudolph, R., Lilie, H., and Jenne, D.E. (2004). Killing of target cells by redirected granzyme B in the absence of perforin. FEBS Lett.562, 87–92.10.1016/S0014-5793(04)00187-5Search in Google Scholar

Kurschus, F.C., Bruno, R., Fellows, E., Falk, C.S., and Jenne, D.E. (2005). Membrane receptors are not required to deliver granzyme B during killer cell attack. Blood105, 2049–2058.10.1182/blood-2004-06-2180Search in Google Scholar PubMed

Lauw, F.N., Simpson, A.J., Hack, C.E., Prins, J.M., Wolbink, A.M., van Deventer, S.J., Chaowagul, W., White, N.J., and van Der Poll, T. (2000). Soluble granzymes are released during human endotoxemia and in patients with severe infection due to Gram-negative bacteria. J. Infect. Dis.182, 206–213.10.1086/315642Search in Google Scholar PubMed

Lieberman, J. (2003). The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat. Rev. Immunol.3, 361–370.10.1038/nri1083Search in Google Scholar

Lieberman, J. and Fan, Z. (2003). Nuclear war: the granzyme A-bomb. Curr. Opin. Immunol.15, 553–559.10.1016/S0952-7915(03)00108-0Search in Google Scholar

Loetscher, P., Seitz, M., Clark-Lewis, I., Baggiolini, M., and Moser, B. (1996). Activation of NK cells by CC chemokines. Chemotaxis, Ca2+ mobilization, and enzyme release. J. Immunol.156, 322–327.Search in Google Scholar

Lohmander, L.S., Neame, P.J., and Sandy, J.D. (1993). The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis. Arthritis Rheum.36, 1214–1222.Search in Google Scholar

Masson, D. and Tschopp, J. (1988). Inhibition of lymphocyte protease granzyme A by antithrombin III. Mol. Immunol.25, 1283–1289.10.1016/0161-5890(88)90043-0Search in Google Scholar

Metkar, S.S., Wang, B., Aguilar-Santelises, M., Raja, S.M., Uhlin-Hansen, L., Podack, E., Trapani, J.A., and Froelich, C.J. (2002). Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity16, 417–428.10.1016/S1074-7613(02)00286-8Search in Google Scholar

Mort, J.S. and Billington, C.J. (2001). Articular cartilage and changes in arthritis: matrix degradation. Arthritis Res.3, 337–341.10.1186/ar325Search in Google Scholar PubMed PubMed Central

Nagase, H. and Kashiwagi, M. (2003). Aggrecanases and cartilage matrix degradation. Arthritis Res. Ther.5, 94–103.10.1186/ar630Search in Google Scholar PubMed PubMed Central

Ohlsson, S., Wieslander, J., and Segelmark, M. (2003). Increased circulating levels of proteinase 3 in patients with anti-neutrophilic cytoplasmic autoantibodies-associated systemic vasculitis in remission. Clin. Exp. Immunol.131, 528–535.10.1046/j.1365-2249.2003.02083.xSearch in Google Scholar PubMed PubMed Central

Ossovskaya, V.S. and Bunnett, N.W. (2004). Protease-activated receptors: contribution to physiology and disease. Physiol. Rev.84, 579–621.10.1152/physrev.00028.2003Search in Google Scholar PubMed

Parry, M.A., Myles, T., Tschopp, J., and Stone, S.R. (1996). Cleavage of the thrombin receptor: identification of potential activators and inactivators. Biochem. J.320, 335–341.10.1042/bj3200335Search in Google Scholar PubMed PubMed Central

Poe, M., Blake, J.T., Boulton, D.A., Gammon, M., Sigal, N.H., Wu, J.K., and Zweerink, H.J. (1991). Human cytotoxic lymphocyte granzyme B. Its purification from granules and the characterization of substrate and inhibitor specificity. J. Biol. Chem.266, 98–103.Search in Google Scholar

Polanska, B., Sidor, D., Leszczyk-Kapusta, I., Niemczuk, M., Paradowska-Jeszke, W., Ciborska, K., and Jankowski, A. (2004). Neutrophil elastase and interleukin-8 as inflammatory mediators in mechanically ventilated children. Med. Sci. Monit.10, CR463–468.Search in Google Scholar

Poole, A.R., Ionescu, M., Swan, A., and Dieppe, P.A. (1994). Changes in cartilage metabolism in arthritis are reflected by altered serum and synovial fluid levels of the cartilage proteoglycan aggrecan. Implications for pathogenesis. J. Clin. Invest.94, 25–33.10.1172/JCI117314Search in Google Scholar PubMed PubMed Central

Preissner, K.T. and Seiffert, D. (1998). Role of vitronectin and its receptors in haemostasis and vascular remodeling. Thromb. Res.89, 1–21.10.1016/S0049-3848(97)00298-3Search in Google Scholar

Raja, S.M., Metkar, S.S., Honing, S., Wang, B., Russin, W.A., Pipalia, N.H., Menaa, C., Belting, M., Cao, X., Dressel, R., and Froelich, C.J. (2005). A novel mechanism for protein delivery: granzyme B undergoes electrostatic exchange from serglycin to target cells. J. Biol. Chem.280, 20752–20761.10.1074/jbc.M501181200Search in Google Scholar

Rissoan, M.C., Duhen, T., Bridon, J.M., Bendriss-Vermare, N., Peronne, C., de Saint Vis, B., Briere, F., and Bates, E.E. (2002). Subtractive hybridization reveals the expression of immunoglobulin-like transcript 7, Eph-B1, granzyme B, and 3 novel transcripts in human plasmacytoid dendritic cells. Blood100, 3295–3303.10.1182/blood-2002-02-0638Search in Google Scholar

Ronday, H.K., van der Laan, W.H., Tak, P.P., de Roos, J.A., Bank, R.A., TeKoppele, J.M., Froelich, C.J., Hack, C.E., Hogendoorn, P.C., Breedveld, F.C., and Verheijen, J.H. (2001). Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis. Rheumatology (Oxford)40, 55–61.10.1093/rheumatology/40.1.55Search in Google Scholar

Rothstein, T.L., Mage, M., Jones, G., and McHugh, L.L. (1978). Cytotoxic T lymphocyte sequential killing of immobilized allogeneic tumor target cells measured by time-lapse microcinematography. J. Immunol.121, 1652–1656.Search in Google Scholar

Rowshani, A.T., Strik, M.C., Molenaar, R., Yong, S.L., Wolbink, A.M., Bemelman, F.J., Hack, C.E., and Ten Berge, I.J. (2005). The granzyme B inhibitor SERPINB9 (protease inhibitor 9) circulates in blood and increases on primary cytomegalovirus infection after renal transplantation. J. Infect. Dis.192, 1908–1911.10.1086/497606Search in Google Scholar

Russell, J.H. and Ley, T.J. (2002). Lymphocyte-mediated cytotoxicity. Annu. Rev. Immunol.20, 323–370.10.1146/annurev.immunol.20.100201.131730Search in Google Scholar

Sanderson, C.J. (1976). The mechanism of T cell mediated cytotoxicity. II. Morphological studies of cell death by time-lapse microcinematography. Proc. R. Soc. Lond. B Biol. Sci.192, 241–255.Search in Google Scholar

Sasson, R., Dantes, A., Tajima, K., and Amsterdam, A. (2003). Novel genes modulated by FSH in normal and immortalized FSH-responsive cells: new insights into the mechanism of FSH action. FASEB J.17, 1256–1266.10.1096/fj.02-0740comSearch in Google Scholar

Sayers, T.J., Wiltrout, T.A., Sowder, R., Munger, W.L., Smyth, M.J., and Henderson, L.E. (1992). Purification of a factor from the granules of a rat natural killer cell line (RNK) that reduces tumor cell growth and changes tumor morphology. Molecular identity with a granule serine protease (RNKP-1). J. Immunol.148, 292–300.Search in Google Scholar

Schwarzbauer, J.E. and Sechler, J.L. (1999). Fibronectin fibrillogenesis: a paradigm for extracellular matrix assembly. Curr. Opin. Cell Biol.11, 622–627.10.1016/S0955-0674(99)00017-4Search in Google Scholar

Seiffert, D. and Smith, J.W. (1997). The cell adhesion domain in plasma vitronectin is cryptic. J. Biol. Chem.272, 13705–13710.10.1074/jbc.272.21.13705Search in Google Scholar PubMed

Shi, L., Keefe, D., Durand, E., Feng, H., Zhang, D., and Lieberman, J. (2005). Granzyme B binds to target cells mostly by charge and must be added at the same time as perforin to trigger apoptosis. J. Immunol.174, 5456–5461.10.4049/jimmunol.174.9.5456Search in Google Scholar PubMed

Simon, M.M., Prester, M., Nerz, G., Kramer, M.D., and Fruth, U. (1988). Release of biologically active fragments from human plasma-fibronectin by murine T cell-specific proteinase 1 (TSP-1). Biol. Chem. Hoppe-Seyler369 (Suppl.), 107–112.Search in Google Scholar

Simon, M.M., Tran, T., Fruth, U., Gurwitz, D., and Kramer, M.D. (1990). Regulation of mouse T cell associated serine proteinase-1 (MTSP-1) by proteinase inhibitors and sulfated polysaccharides. Biol. Chem. Hoppe-Seyler371 (Suppl.), 81–87.Search in Google Scholar

Simon, M.M., Kramer, M.D., Prester, M., and Gay, S. (1991). Mouse T-cell associated serine proteinase 1 degrades collagen type IV: a structural basis for the migration of lymphocytes through vascular basement membranes. Immunology73, 117–119.Search in Google Scholar

Skold, S., Zeberg, L., Gullberg, U., and Olofsson, T. (2002). Functional dissociation between proforms and mature forms of proteinase 3, azurocidin, and granzyme B in regulation of granulopoiesis. Exp. Hematol.30, 689–696.10.1016/S0301-472X(02)00816-0Search in Google Scholar

Smyth, M.J., McGuire, M.J., and Thia, K.Y. (1995). Expression of recombinant human granzyme B. A processing and activation role for dipeptidyl peptidase I. J. Immunol.154, 6299–6305.Search in Google Scholar

Sower, L.E., Froelich, C.J., Allegretto, N., Rose, P.M., Hanna, W.D., and Klimpel, G.R. (1996a). Extracellular activities of human granzyme A. Monocyte activation by granzyme A versus α-thrombin. J. Immunol.156, 2585–2590.Search in Google Scholar

Sower, L.E., Klimpel, G.R., Hanna, W., and Froelich, C.J. (1996b). Extracellular activities of human granzymes. I. Granzyme A induces IL6 and IL8 production in fibroblast and epithelial cell lines. Cell. Immunol.171, 159–163.10.1006/cimm.1996.0187Search in Google Scholar

Spaeny-Dekking, E.H., Hanna, W.L., Wolbink, A.M., Wever, P.C., Kummer, A.J., Swaak, A.J., Middeldorp, J.M., Huisman, H.G., Froelich, C.J.. and Hack, C.E. (1998). Extracellular granzymes A and B in humans: detection of native species during CTL responses in vitro and in vivo. J. Immunol.160, 3610–3616.Search in Google Scholar

Spaeny-Dekking, E.H., Kamp, A.M., Froelich, C.J., and Hack, C.E. (2000). Extracellular granzyme A, complexed to proteoglycans, is protected against inactivation by protease inhibitors. Blood95, 1465–1472.10.1182/blood.V95.4.1465.004k13_1465_1472Search in Google Scholar

Stanton, H., Ung, L., and Fosang, A.J. (2002). The 45 kDa collagen-binding fragment of fibronectin induces matrix metalloproteinase-13 synthesis by chondrocytes and aggrecan degradation by aggrecanases. Biochem. J.364, 181–190.10.1042/bj3640181Search in Google Scholar

Suidan, H.S., Bouvier, J., Schaerer, E., Stone, S.R., Monard, D., and Tschopp, J. (1994). Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Proc. Natl. Acad. Sci. USA91, 8112–8116.10.1073/pnas.91.17.8112Search in Google Scholar

Suidan, H.S., Clemetson, K.J., Brown-Luedi, M., Niclou, S.P., Clemetson, J.M., Tschopp, J., and Monard, D. (1996). The serine protease granzyme A does not induce platelet aggregation but inhibits responses triggered by thrombin. Biochem. J.315, 939–945.10.1042/bj3150939Search in Google Scholar

Sun, J., Bird, C.H., Sutton, V., McDonald, L., Coughlin, P.B., De Jong, T.A., Trapani, J.A., and Bird, P.I. (1996). A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes. J. Biol. Chem.271, 27802–27809.10.1074/jbc.271.44.27802Search in Google Scholar

Tak, P.P., Spaeny-Dekking, L., Kraan, M.C., Breedveld, F.C., Froelich, C.J., and Hack, C.E. (1999). The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA). Clin. Exp. Immunol.116, 366–370.Search in Google Scholar

Takahashi, K., Nakamura, T., Adachi, H., Yagita, H., and Okumura, K. (1991). Antigen-independent T cell activation mediated by a very late activation antigen-like extracellular matrix receptor. Eur. J. Immunol.21, 1559–1562.10.1002/eji.1830210634Search in Google Scholar

Taub, D.D., Sayers, T.J., Carter, C.R., and Ortaldo, J.R. (1995). α and β chemokines induce NK cell migration and enhance NK-mediated cytolysis. J. Immunol.155, 3877–3888.Search in Google Scholar

Taub, D.D., Ortaldo, J.R., Turcovski-Corrales, S.M., Key, M.L., Longo, D.L., and Murphy, W.J. (1996). Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production. J. Leukoc. Biol.59, 81–89.10.1002/jlb.59.1.81Search in Google Scholar

ten Berge, I.J., Wever, P.C., Wolbink, A.M., Surachno, J., Wertheim, P.M., Spaeny, L.H., and Hack, C.E. (1998). Increased systemic levels of soluble granzymes A and B during primary cytomegalovirus infection after renal transplantation. Transplant Proc.30, 3972–3974.10.1016/S0041-1345(98)01308-6Search in Google Scholar

Tremblay, G.M., Wolbink, A.M., Cormier, Y., and Hack, C.E. (2000). Granzyme activity in the inflamed lung is not controlled by endogenous serine proteinase inhibitors. J. Immunol.165, 3966–3969.10.4049/jimmunol.165.7.3966Search in Google Scholar

Triantafilou, K., Takada, Y., and Triantafilou, M. (2001). Mechanisms of integrin-mediated virus attachment and internalization process. Crit. Rev. Immunol.21, 311–322.10.1615/CritRevImmunol.v21.i4.10Search in Google Scholar

Vacca, A., Ria, R., Presta, M., Ribatti, D., Iurlaro, M., Merchionne, F., Tanghetti, E., and Dammacco, F. (2001). α(v)β(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells. Exp. Hematol.29, 993–1003.10.1016/S0301-472X(01)00674-9Search in Google Scholar

van Woensel, J.B., Biezeveld, M.H., Hack, C.E., Bos, A.P., and Kuijpers, T.W. (2005). Elastase and granzymes during meningococcal disease in children: correlation to disease severity. Intensive Care Med.31, 1239–1247.10.1007/s00134-005-2720-3Search in Google Scholar PubMed

Vanguri, P., Lee, E., Henkart, P., and Shin, M.L. (1993). Hydrolysis of myelin basic protein in myelin membranes by granzymes of large granular lymphocytes. J. Immunol.150, 2431–2439.Search in Google Scholar

Vettel, U., Brunner, G., Bar-Shavit, R., Vlodavsky, I., and Kramer, M.D. (1993). Charge-dependent binding of granzyme A (MTSP-1) to basement membranes. Eur. J. Immunol.23, 279–282.10.1002/eji.1830230144Search in Google Scholar PubMed

Veugelers, K., Motyka, B., Goping, I.S., Shostak, I., Sawchuk, T., and Bleackley, R.C. (2006). Granule-mediated killing by granzyme B and perforin requires a mannose 6-phosphate receptor and is augmented by cell surface heparan sulfate. Mol. Biol. Cell17, 623–633.10.1091/mbc.e05-07-0631Search in Google Scholar PubMed PubMed Central

Wowk, M.E. and Trapani, J.A. (2004). Cytotoxic activity of the lymphocyte toxin granzyme B. Microbes Infect.6, 752–758.10.1016/j.micinf.2004.03.008Search in Google Scholar PubMed

Xu, B., Sakkas, L.I., Slachta, C.A., Goldman, B.I., Jeevanandam, V., Oleszak, E.L., and Platsoucas, C.D. (2001). Apoptosis in chronic rejection of human cardiac allografts. Transplantation71, 1137–1146.10.1097/00007890-200104270-00022Search in Google Scholar PubMed

Ybarrondo, B., O'Rourke, A.M., McCarthy, J.B., and Mescher, M.F. (1997). Cytotoxic T-lymphocyte interaction with fibronectin and vitronectin: activated adhesion and cosignalling. Immunology91, 186–192.10.1046/j.1365-2567.1997.00237.xSearch in Google Scholar PubMed PubMed Central

Young, L.H., Joag, S.V., Lin, P.Y., Luo, S.F., Zheng, L.M., Liu, C.C., and Young, J.D. (1992). Expression of cytolytic mediators by synovial fluid lymphocytes in rheumatoid arthritis. Am. J. Pathol.140, 1261–1268.Search in Google Scholar

Yurchenco, P.D. and Schittny, J.C. (1990). Molecular architecture of basement membranes. FASEB J.4, 1577–1590.10.1096/fasebj.4.6.2180767Search in Google Scholar PubMed

Published Online: 2006-07-20
Published in Print: 2006-07-01

©2006 by Walter de Gruyter Berlin New York