International Archives of Allergy and Immunology
Original Paper
Granzyme H Is a Novel Protease Expressed by Human Mast CellsRönnberg E.a · Calounova G.a · Sutton V.R.c · Trapani J.A.c · Rollman O.b · Hagforsen E.b · Pejler G.aaDepartment of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, and bDepartment of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden; cSir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vic., Australia
Keywords: Granzyme HMast cellsProteases |
|
Log in to MyKarger to check if you already have access to this content.
KAB
Buy a Karger Article Bundle (KAB) and profit from a discount!
If you would like to redeem your KAB credit, please log in.
Save over 20% compared to the individual article price.
Article / Publication Details
Received: February 19, 2014
Accepted: September 12, 2014
Published online: October 21, 2014
Issue release date: November 2014
Number of Print Pages: 7
Number of Figures: 4
Number of Tables: 0
ISSN: 1018-2438 (Print)
eISSN: 1423-0097 (Online)
For additional information: https://www.karger.com/IAA
Abstract
Background: Many of the functions attributed to mast cells depend on the various pro-inflammatory mediators that are secreted upon mast cell activation. These include a panel of mast cell-specific proteases. In addition, recent studies have indicated that murine mast cells also express granzyme D, a protease previously thought to be confined to cytotoxic lymphocytes. Here, we address the human relevance of the latter findings by investigating whether human mast cells express granzyme H, the granzyme that may represent the functional counterpart to murine granzyme D. Methods: Cord blood-derived mast cells, LAD2 cells and skin mast cells in situ were evaluated for their expression of granzymes using quantitative PCR, Western blot analysis and immunostaining. Mast cells were activated by either calcium ionophore stimulation or IgE receptor cross-linking. Results: Cord blood-derived mast cells and LAD2 cells were shown to express granzyme H and B mRNA, while granzyme A, K and M expression was undetectable. Mast cell activation by either calcium ionophore or IgE receptor cross-linking caused down-regulated expression of granzyme H. In contrast, granzyme B expression was up-regulated by the same stimuli. Granzyme H expression was also confirmed at the protein level, as shown by both Western blot analysis and confocal microscopy. Further, we show that granzyme H is expressed by human skin mast cells in situ. Conclusions: The present findings implicate granzyme H as a novel protease expressed by human mast cells and support earlier findings obtained in natural killer cells suggesting that granzymes B and H are reciprocally regulated.
© 2014 S. Karger AG, Basel
Related Articles:
References
- Galli SJ, Grimbaldeston M, Tsai M: Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 2008;8:478-486.
- Metz M, Maurer M: Mast cells - key effector cells in immune responses. Trends Immunol 2007;28:234-241.
- Dawicki W, Marshall JS: New and emerging roles for mast cells in host defence. Curr Opin Immunol 2007;19:31-38.
- Pejler G, Åbrink M, Ringvall M, Wernersson S: Mast cell proteases. Adv Immunol 2007;95:167-255.
- Wernersson S, Pejler G: Mast cell granules: armed for battle. Nat Rev Immunol 2014;14:478-494.
- Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R: Mast cells: a unique source of renin. Proc Natl Acad Sci U S A 2004;101:13607-13612.
- Schechter NM, Irani AM, Sprows JL, Abernethy J, Wintroub B, Schwartz LB: Identification of a cathepsin G-like proteinase in the MCTC type of human mast cell. J Immunol 1990;145:2652-2661.
- Baram D, Vaday GG, Salamon P, Drucker I, Hershkoviz R, Mekori YA: Human mast cells release metalloproteinase-9 on contact with activated T cells: juxtacrine regulation by TNF-alpha. J Immunol 2001;167:4008-4016.
- Garcia-Faroldi G, Rönnberg E, Orro A, Calounova G, Guss B, Lundequist A, Pejler G: ADAMTS: novel proteases expressed by activated mast cells. Biol Chem 2013;394:291-305.
- Maaninka K, Lappalainen J, Kovanen PT: Human mast cells arise from a common circulating progenitor. J Allergy Clin Immunol 2013;132:463.e3-469.e3.
- Pardo J, Wallich R, Ebnet K, Iden S, Zentgraf H, Martin P, Ekiciler A, Prins A, Mullbacher A, Huber M, Simon MM: Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin. Cell Death Differ 2007;14:1768-1779.
- Strik MC, de Koning PJ, Kleijmeer MJ, Bladergroen BA, Wolbink AM, Griffith JM, Wouters D, Fukuoka Y, Schwartz LB, Hack CE, van Ham SM, Kummer JA: Human mast cells produce and release the cytotoxic lymphocyte associated protease granzyme B upon activation. Mol Immunol 2007;44:3462-3472.
- Anthony DA, Andrews DM, Watt SV, Trapani JA, Smyth MJ: Functional dissection of the granzyme family: cell death and inflammation. Immunol Rev 2010;235:73-92.
- Rönnberg E, Calounova G, Guss B, Lundequist A, Pejler G: Granzyme D is a novel murine mast cell protease that is highly induced by multiple pathways of mast cell activation. Infect Immun 2013;81:2085-2094.
- Rönnberg E, Guss B, Pejler G: Infection of mast cells with live streptococci causes a toll-like receptor 2- and cell-cell contact-dependent cytokine and chemokine response. Infect Immun 2010;78:854-864.
- Edwards KM, Kam CM, Powers JC, Trapani JA: The human cytotoxic T cell granule serine protease granzyme H has chymotrypsin-like (chymase) activity and is taken up into cytoplasmic vesicles reminiscent of granzyme B-containing endosomes. J Biol Chem 1999;274:30468-30473.
- Froelich CJ, Pardo J, Simon MM: Granule-associated serine proteases: granzymes might not just be killer proteases. Trends Immunol 2009;30:117-123.
- Plasman K, Maurer-Stroh S, Ahmad J, Hao H, Kaiserman D, Sirota FL, Jonckheere V, Bird PI, Gevaert K, Van Damme P: Conservation of the extended substrate specificity profiles among homologous granzymes across species. Mol Cell Proteomics 2013;12:2921-2934.
- Kirshenbaum AS, Akin C, Wu Y, Rottem M, Goff JP, Beaven MA, Rao VK, Metcalfe DD: Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of FcepsilonRI or FcgammaRI. Leuk Res 2003;27:677-682.
- Sedelies KA, Sayers TJ, Edwards KM, Chen W, Pellicci DG, Godfrey DI, Trapani JA: Discordant regulation of granzyme H and granzyme B expression in human lymphocytes. J Biol Chem 2004;279:26581-26587.
- Lundequist A, Calounova G, Wensman H, Ronnberg E, Pejler G: Differential regulation of Nr4a subfamily nuclear receptors following mast cell activation. Mol Immunol 2011;48:1753-1761.
- Rivera J, Fierro NA, Olivera A, Suzuki R: New insights on mast cell activation via the high affinity receptor for IgE. Adv Immunol 2008;98:85-120.
- Fellows E, Gil-Parrado S, Jenne DE, Kurschus FC: Natural killer cell-derived human granzyme H induces an alternative, caspase-independent cell-death program. Blood 2007;110:544-552.
- Hou Q, Zhao T, Zhang H, Lu H, Zhang Q, Sun L, Fan Z: Granzyme H induces apoptosis of target tumor cells characterized by DNA fragmentation and Bid-dependent mitochondrial damage. Mol Immunol 2008;45:1044-1055.
- Benyon RC, Bissonnette EY, Befus AD: Tumor necrosis factor-alpha dependent cytotoxicity of human skin mast cells is enhanced by anti-IgE antibodies. J Immunol 1991;147:2253-2258.
- Dery RE, Lin TJ, Befus AD, Milne CD, Moqbel R, Menard G, Bissonnette EY: Redundancy or cell-type-specific regulation? Tumour necrosis factor in alveolar macrophages and mast cells. Immunology 2000;99:427-434.
- Law RH, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, Dunstone MA, D'Angelo ME, Orlova EV, Coulibaly F, Verschoor S, Browne KA, Ciccone A, Kuiper MJ, Bird PI, Trapani JA, Saibil HR, Whisstock JC: The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 2010;468:447-451.
- Buzza MS, Zamurs L, Sun J, Bird CH, Smith AI, Trapani JA, Froelich CJ, Nice EC, Bird PI: Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. J Biol Chem 2005;280:23549-23558.
- Suidan HS, Bouvier J, Schaerer E, Stone SR, Monard D, Tschopp J: Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Proc Natl Acad Sci U S A 1994;91:8112-8116.
- Andrade F, Fellows E, Jenne DE, Rosen A, Young CS: Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition. EMBO J 2007;26:2148-2157.
- Tang H, Li C, Wang L, Zhang H, Fan Z: Granzyme H of cytotoxic lymphocytes is required for clearance of the hepatitis B virus through cleavage of the hepatitis B virus X protein. J Immunol 2012;188:824-831.
- Romero V, Fellows E, Jenne DE, Andrade F: Cleavage of La protein by granzyme H induces cytoplasmic translocation and interferes with La-mediated HCV-IRES translational activity. Cell Death Differ 2009;16:340-348.
Article / Publication Details
Received: February 19, 2014
Accepted: September 12, 2014
Published online: October 21, 2014
Issue release date: November 2014
Number of Print Pages: 7
Number of Figures: 4
Number of Tables: 0
ISSN: 1018-2438 (Print)
eISSN: 1423-0097 (Online)
For additional information: https://www.karger.com/IAA
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Get Permission