Background: Allergic asthma is a Th2-type chronic inflammatory disease of the lung. It is characterized by infiltration of eosinophils, neutrophils, mast cells and T lymphocytes into the airways. Th2 cytokines like interleukin (IL)-4, IL-5 and chemokines like eotaxin are increased in the asthmatic response. The processing and presentation of exogenous antigens is important in the sensitization to an allergen. Cathepsin E (Ctse) is an intracellular aspartic endoprotease which is expressed in immune cells like dendritic cells (DCs). It was found to play an essential role in the processing and presentation of ovalbumin (OVA). The aim of the present study was to investigate the inhibition of Ctse in two different experimental models of allergic airway inflammation. Methods: Ctse wild-type (Ctse+/+) and Ctse-deficient (Ctse–/–) bone marrow-derived DCs (BMDCs) were pulsed with OVA/OVA peptide and cocultured with OVA transgenic T II (OT II) cells whose proliferation was subsequently analyzed. Two different in vivo asthma models with Ctse+/+ and Ctse–/– mice were performed: an acute OVA-induced and a subchronic Phleum pratense-induced airway inflammation. Results: Proliferation of OT II cells was decreased when cocultured with BMDCs of Ctse–/– mice as compared to cells cocultured with BMDCs of Ctse+/+ mice. In vivo, Ctse deficiency led to reduced lymphocyte influx after allergen sensitization and challenge in both investigated airway inflammation models, compared to their control groups. Conclusion: Ctse deficiency leads to a reduced antigen presentation in vitro. This is followed by a distinct effect on lymphocyte influx in states of allergic airway inflammation in vivo.

Keywords:
Dendritic cell, Airway inflammation, Cathepsin E
1.
Kageyama T, Takahashi K: A cathepsin D-like acid proteinase from human gastric mucosa: purification and characterization. J Biochem 1980;87:725–735.
2.
Zaidi N, Kalbacher H: Cathepsin E: a mini review. Biochem Biophys Res Commun 2008;367:517–522.
3.
Chain BM, Free P, Medd P, Swetman C, Tabor AB, Terrazzini N: The expression and function of cathepsin E in dendritic cells. J Immunol 2005;174:1791–1800.
4.
Zaidi N, Hermann C, Herrmann T, Kalbacher H: Emerging functional roles of cathepsin E. Biochem Biophys Res Commun 2008;377:327–330.
5.
Sastradipura DF, Nakanishi H, Tsukuba T, Nishishita K, Sakai H, Kato Y, Gotow T, Uchiyama Y, Yamamoto K: Identification of cellular compartments involved in processing of cathepsin E in primary cultures of rat microglia. J Neurochem 1998;70:2045–2056.
6.
Solcia E, Paulli M, Silini E, Fiocca R, Finzi G, Kindl S, Boveri E, Bosi F, Cornaggia M, Capella C: Cathepsin E in antigen-presenting Langerhans and interdigitating reticulum cells: its possible role in antigen processing. Eur J Histochem 1993;37:19–26.
7.
Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, Koster A, Hess B, Evers M, von Figura K: Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 1995;14:3599–3608.
8.
Yoshimine Y, Tsukuba T, Isobe R, Sumi M, Akamine A, Maeda K, Yamamoto K: Specific immunocytochemical localization of cathepsin E at the ruffled border membrane of active osteoclasts. Cell Tissue Res 1995;281:85–91.
9.
Zaidi N, Herrmann T, Baechle D, Schleicher S, Gogel J, Driessen C, Voelter W, Kalbacher H: A new approach for distinguishing cathepsin E and D activity in antigen-processing organelles. FEBS J 2007;274:3138–3149.
10.
Saku T, Sakai H, Shibata Y, Kato Y, Yamamoto K: An immunocytochemical study on distinct intracellular localization of cathepsin E and cathepsin D in human gastric cells and various rat cells. J Biochem 1991;110:956–964.
11.
Tsukuba T, Hori H, Azuma T, Takahashi T, Taggart RT, Akamine A, Ezaki M, Nakanishi H, Sakai H, Yamamoto K: Isolation and characterization of recombinant human cathepsin E expressed in Chinese hamster ovary cells. J Biol Chem 1993;268:7276–7282.
12.
Tsukuba T, Okamoto K, Okamoto Y, Yanagawa M, Kohmura K, Yasuda Y, Uchi H, Nakahara T, Furue M, Nakayama K, Kadowaki T, Yamamoto K, Nakayama KI: Association of cathepsin E deficiency with development of atopic dermatitis. J Biochem 2003;134:893–902.
13.
Tsukuba T, Yamamoto S, Yanagawa M, Okamoto K, Okamoto Y, Nakayama KI, Kadowaki T, Yamamoto K: Cathepsin E-deficient mice show increased susceptibility to bacterial infection associated with the decreased expression of multiple cell surface Toll-like receptors. J Biochem 2006;140:57–66.
14.
Bennett K, Levine T, Ellis JS, Peanasky RJ, Samloff IM, Kay J, Chain BM: Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E. Eur J Immunol 1992;22:1519–1524.
15.
Nishioku T, Hashimoto K, Yamashita K, Liou SY, Kagamiishi Y, Maegawa H, Katsube N, Peters C, von Figura K, Saftig P, Katunuma N, Yamamoto K, Nakanishi H: Involvement of cathepsin E in exogenous antigen processing in primary cultured murine microglia. J Biol Chem 2002;277:4816–4822.
16.
Pavli P, Maxwell L, Van de PE, Doe F: Distribution of human colonic dendritic cells and macrophages. Clin Exp Immunol 1996;104:124–132.
17.
Sertl K, Takemura T, Tschachler E, Ferrans VJ, Kaliner MA, Shevach EM: Dendritic cells with antigen-presenting capability reside in airway epithelium, lung parenchyma, and visceral pleura. J Exp Med 1986;163:436–451.
18.
Upham JW, Stumbles PA: Why are dendritic cells important in allergic diseases of the respiratory tract? Pharmacol Ther 2003;100:75–87.
19.
Bryant P, Ploegh H: Class II MHC peptide loading by the professionals. Curr Opin Immunol 2004;16:96–102.
20.
Wilson NS, Villadangos JA: Regulation of antigen presentation and cross-presentation in the dendritic cell network: facts, hypothesis, and immunological implications. Adv Immunol 2005;86:241–305.
21.
Bryant P, Ploegh H: Class II MHC peptide loading by the professionals. Curr Opin Immunol 2004;16:96–102.
22.
Honey K, Rudensky AY: Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol 2003;3:472–482.
23.
Moss CX, Villadangos JA, Watts C: Destructive potential of the aspartyl protease cathepsin D in MHC class II-restricted antigen processing. Eur J Immunol 2005;35:3442–3451.
24.
Lambrecht BN, Hammad H: Lung dendritic cells: targets for therapy in allergic disease. Chem Immunol Allergy 2008;94:189–200.
25.
Masoli M, Fabian D, Holt S, Beasley R: The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59:469–478.
26.
Marks GB, Correll PK, Williamson M: Asthma in Australia 2005. Med J Aust 2005;183:445–446.
27.
van Rijt LS, Lambrecht BN: Dendritic cells in asthma: a function beyond sensitization. Clin Exp Allergy 2005;35:1125–1134.
28.
Vermaelen KY, Carro-Muino I, Lambrecht BN, Pauwels RA: Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J Exp Med 2001;193:51–60.
29.
Lambrecht BN, Salomon B, Klatzmann D, Pauwels RA: Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. J Immunol 1998;160:4090–4097.
30.
Marathias KP, Preffer FI, Pinto C, Kradin RL: Most human pulmonary infiltrating lymphocytes display the surface immune phenotype and functional responses of sensitized T cells. Am J Respir Cell Mol Biol 1991;5:470–476.
31.
Medoff BD, Thomas SY, Banerji A, Wain JC, Zhang H, Lilly CM, Ginns LC, Luster AD: Pathogenic T cell recruitment into the airway in human disease. Ann NY Acad Sci 2005;1062:220–241.
32.
Medoff BD, Thomas SY, Luster AD: T cell trafficking in allergic asthma: the ins and outs. Annu Rev Immunol 2008;26:205–232.
33.
Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, Schuler G: An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 1999;223:77–92.
34.
Nassenstein C, Kammertoens T, Veres TZ, Uckert W, Spies E, Fuchs B, Krug N, Braun A: Neuroimmune crosstalk in asthma: dual role of the neurotrophin receptor p75NTR. J Allergy Clin Immunol 2007;120:1089–1096.
35.
Fuchs B, Knothe S, Rochlitzer S, Nassimi M, Greweling M, Lauenstein HD, Nassenstein C, Muller M, Ebensen T, Dittrich AM, Krug N, Guzman CA, Braun A: A Toll-like receptor 2/6 agonist reduces allergic airway inflammation in chronic respiratory sensitisation to Timothy grass pollen antigens. Int Arch Allergy Immunol 2010;152:131–139.
36.
Kakehashi H, Nishioku T, Tsukuba T, Kadowaki T, Nakamura S, Yamamoto K: Differential regulation of the nature and functions of dendritic cells and macrophages by cathepsin E. J Immunol 2007;179:5728–5737.
37.
Yee CS, Yao Y, Li P, Klemsz MJ, Blum JS, Chang CH: Cathepsin E: a novel target for regulation by class II transactivator. J Immunol 2004;172:5528–5534.
38.
Chang CH, Hong SC, Hughes CC, Janeway CA Jr, Flavell RA: CIITA activates the expression of MHC class II genes in mouse T cells. Int Immunol 1995;7:1515–1518.
39.
Tsukuba T, Yanagawa M, Okamoto K, Okamoto Y, Yasuda Y, Nakayama KI, Kadowaki T, Yamamoto K: Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages. J Biochem 2009;145:565–573.
40.
Bloemen K, Verstraelen S, Van Den HR, Witters H, Nelissen I, Schoeters G: The allergic cascade: review of the most important molecules in the asthmatic lung. Immunol Lett 2007;113:6–18.
41.
Moss CX, Villadangos JA, Watts C: Destructive potential of the aspartyl protease cathepsin D in MHC class II-restricted antigen processing. Eur J Immunol 2005;35:3442–3451.
42.
Tulone C, Tsang J, Prokopowicz Z, Grosvenor N, Chain B: Natural cathepsin E deficiency in the immune system of C57BL/6J mice. Immunogenetics 2007;59:927–935.
43.
Hsing LC, Rudensky AY: The lysosomal cysteine proteases in MHC class II antigen presentation. Immunol Rev 2005;207:229–241.
44.
van Eijk M, van Noorden CJ, de Groot C: Proteinases and their inhibitors in the immune system. Int Rev Cytol 2003;222:197–236.
45.
Hewitt EW, Treumann A, Morrice N, Tatnell PJ, Kay J, Watts C: Natural processing sites for human cathepsin E and cathepsin D in tetanus toxin: implications for T cell epitope generation. J Immunol 1997;159:4693–4699.
46.
Rhodes JM, Andersen AB: Role of cathepsin D in the degradation of human serum albumin by peritoneal macrophages and veiled cells in antigen presentation. Immunol Lett 1993;37:103–110.
47.
Burster T, Giffon T, Dahl ME, Bjorck P, Bogyo M, Weber E, Mahmood K, Lewis DB, Mellins ED: Influenza A virus elevates active cathepsin B in primary murine DC. Int Immunol 2007;19:645–655.
48.
Zhang T, Maekawa Y, Hanba J, Dainichi T, Nashed BF, Hisaeda H, Sakai T, Asao T, Himeno K, Good RA, Katunuma N: Lysosomal cathepsin B plays an important role in antigen processing, while cathepsin D is involved in degradation of the invariant chain inovalbumin-immunized mice. Immunology 2000;100:13–20.
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2012
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