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J. Biol. Chem., Vol. 277, Issue 7, 4816-4822, February 15, 2002

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Involvement of Cathepsin E in Exogenous Antigen Processing in Primary Cultured Murine Microglia^*

Tsuyoshi Nishioku^§, Koichi Hashimoto^¶, Keizo Yamashita^¶, Shyh-Yuh Liou^¶, Yoshifumi Kagamiishi, Hitoshi Maegawa, Nobuo Katsube, Christoph Peters^**, Kurt von Figura, Paul Saftig, Nobuhiko Katunuma^§§, Kenji Yamamoto, and Hiroshi Nakanishi^§¶¶

From the  Department of Pharmacology, Graduate School of Dental Science and ^§ Laboratory of Oral Aging Science, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan, the ^¶ Tsukuba Research Laboratories, Nippon Glaxo Ltd., Tsukuba 300-4247, Japan, the  Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan, the ^** Institute für Molekulare Medizin und Zellforschung, Albert-Ludwings-Universität Freiburg Hugstetter Strasse 55, 79106 Freiburg, Germany, the  Center for Biochemistry and Molecular Cell Biology, Göttingen University, Heinrich-Düker Weg 12, 37037 Göttingen, Germany, and the ^§§ Tokushima Bunri University, Institute for Health Sciences, Tokushima 770-8514, Japan

We have attempted to elucidate an involvement of cathepsin E (CE) in major histocompatibility complex class II-mediated antigen presentation by microglia. In primary cultured murine microglia, CE was localized mainly in early endosomes and its expression level was markedly increased upon stimulation with interferon-. Pepstatin A, a specific inhibitor of aspartic proteases, significantly inhibited interleukin-2 production from an OVA-(266-281)-specific T helper cell hybridomas upon stimulation with native OVA presented by interferon--treated microglia. However, pepstatin A failed to inhibit the presentation of OVA-(266-281) peptide. The possible involvement of CE in the processing of native OVA into antigenic peptide was further substantiated by that digested fragments of native OVA by CE could be recognized by OVA-specific Th cells. Cathepsin D also degraded native OVA into antigenic peptide, whereas microglia prepared from cathepsin D-deficient mice retained an ability for antigen presentation. On the other hand, the requirement for cysteine proteases such as cathepsins S and B in the processing of invariant chain (Ii) was confirmed by immunoblot analyses in the presence of their specific inhibitors. In conclusion, CE is required for the generation of an antigenic epitope from OVA but not for the processing of Ii in microglia.

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