title: Cathepsin L is crucial for a Th1-type immune response during Leishmania major infection.
abstract: Prior to the activation of CD4+ T cells, exogenous proteins are digested by endo/lysosomal enzymes in antigen-presenting cells (APCs) to produce antigenic peptides that are presented on MHC class II molecules. In the studies described here, the functional significance of cathepsin L for antigen processing and Th1/Th2 differentiation in experimental leishmaniasis was investigated. We first demonstrated that cathepsin L is one of the candidates for endo/lysosomal enzymes in the processing of soluble Leishmania antigen (SLA) by using CLIK148, a specific inhibitor of cathepsin L. Treatment of BALB/c or DBA/2 mice with CLIK148 exacerbated the disease by enhancing an SLA-specific Th2-type response such as IL-4 production. CLIK148 did not exert any direct influence on Leishmania major promastigotes themselves or on the course of L. major infection in SCID mice. Taken together, these findings suggest that treatment of host mice with CLIK148 affects the processing of SLA in APCs, resulting in the potentiation of Th2-type immune responses and thus leading to exacerbation of the disease. Furthermore, endo/lysosomal cathepsin L was found to be functionally distinct from previously described cathepsins B and D.
authors.affiliation: Department Microbiology and Immunology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. koonishi@jikei.ac.jp
authors.forename: Kotaro
authors.initials: K
authors.lastname: Onishi
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Kazunari
authors.initials: K
authors.lastname: Ishii
authors.forename: Hajime
authors.initials: H
authors.lastname: Hisaeda
authors.forename: Lijun
authors.initials: L
authors.lastname: Tang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Duan
authors.forename: Teruki
authors.initials: T
authors.lastname: Dainichi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: Kunisuke
authors.initials: K
authors.lastname: Himeno
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000953:Antigens, Protozoan / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004852:Epoxy Compounds / Q000494:pharmacology; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011480:Protease Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; C402823:CLIK 148; D004151:Dipeptides; D004852:Epoxy Compounds; D007074:Immunoglobulin G; D011480:Protease Inhibitors; D011725:Pyridines; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534278:Ctsl protein, mouse