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Differential Regulation of the Nature and Functions of Dendritic Cells and Macrophages by Cathepsin E

Hiroe Kakehashi^*,, Tsuyoshi Nishioku^1,*, Takayuki Tsukuba^2,*, Tomoko Kadowaki^*, Seiji Nakamura and Kenji Yamamoto^3,*

^* Department of Pharmacology and Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan

The aspartic proteinase cathepsin E is localized mainly in the endosomal structures of APCs and has been implicated in a variety of immune responses, however, the precise roles of cathepsin E in these cells remain speculative. In this study, we report the effect of disrupting the gene encoding cathepsin E on the nature and functions of dendritic cells (DCs) and macrophages derived from mouse bone marrow precursors, as well as mouse peritoneal macrophages. Whereas cathepsin E deficiency induced the accumulation of the lysosome-associated membrane protein (LAMP)-1 and LAMP-2 and elevated the lysosomal pH in macrophages, it did not have these effects on DCs. Although cathepsin E deficiency also caused a marked decrease in degradation of phagocytosed OVA and chemotactic responses to MCP-1 and fMLP by macrophages, these abilities were little affected in DCs by the absence of cathepsin E. Interestingly, cathepsin E deficiency markedly decreased the ability of macrophages to present intact OVA, as well as an OVA-derived antigenic peptide (266–281), to cognate T cells, while that of DCs was inversely enhanced by the absence of this protein. This paradox was resolved, in part, by the enhanced phagocytic activity and the increased expression of the costimulatory molecules CD86, CD80, and CD40, which amplify the response of T cells, in cathepsin E-deficient DCs compared with the wild-type cells. These results indicate that cathepsin E differentially regulates the nature and function of DCs and macrophages.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Department of Pharmaceutical Care and Health Sciences, Fukuoka University Pharmaceutical Sciences, Jonan-ku, Fukuoka 814-0181, Japan.

² Current address: Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.

³ Address correspondence and reprint requests to Dr. Kenji Yamamoto, Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. E-mail address: kyama{at}dent.kyushu-u.ac.jp

⁴ Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; Ii, invariant chain; LAMP, lysosome-associated membrane protein.

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