Cathepsin L is crucial for a Th1-type immune response during Leishmania major infection.
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.
Onishi
Kotaro
K
Department Microbiology and Immunology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. koonishi@jikei.ac.jp
Li
Yang
Y
Ishii
Kazunari
K
Hisaeda
Hajime
H
Tang
Lijun
L
Duan
Xuefeng
X
Dainichi
Teruki
T
Maekawa
Yoichi
Y
Katunuma
Nobuhiko
N
Himeno
Kunisuke
K
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
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