title: Cathepsin E-deficient mice show increased susceptibility to bacterial infection associated with the decreased expression of multiple cell surface Toll-like receptors.
abstract: Cathepsin E, an intracellular aspartic proteinase, is predominantly localized in the endosomal compartments of immune system cells. In the present study, we investigated the role of cathepsin E in immune defense systems against bacterial infection. Cathepsin E-deficient (CatE(-/-)) mice showed dramatically increased susceptibility to infection with both the Gram-positive bacterium Staphyrococcus aureus, and the Gram-negative bacterium Porphyromonas gingivalis when compared with syngeneic wild-type mice, most likely due to impaired regulation of bacterial elimination. Peritoneal macrophages from CatE(-/-) mice showed significantly impaired tumor necrosis factor-alpha and IL-6 production in response to S. aureus and decreased bactericidal activities toward this bacterium. Moreover, the cell surface levels of Toll-like receptor-2 (TLR2) and TLR4, which recognize specific components of Gram-positive and -negative bacteria, respectively, were decreased in CatE(-/-) macrophages, despite no significant difference in the total cellular expression levels of these receptors between the wild-type and CatE(-/-) macrophages, implying trafficking defects in these surface receptors in the latter. These results indicate an essential role of cathepsin E in immune defense against invading microorganisms, most probably due to regulation of the cell surface expression of TLR family members required for innate immune responses.
authors.affiliation: Departments of Pharmacology, Pediatric Dentistry, and Fixed Prosthodontics, Graduate School of Dental Science, Kyushu University, Fukuoka 812-8582.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsukuba
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yanagawa
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Okamoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000209:etiology*; D020059:Cathepsin E / Q000172:deficiency*; D020022:Genetic Predisposition to Disease; D015850:Interleukin-6 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport / Q000235:genetics; D013203:Staphylococcal Infections / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015850:Interleukin-6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D020059:Cathepsin E