Treatment with cathepsin L inhibitor potentiates Th2-type immune response in Leishmania major-infected BALB/c mice.
Prior to the activation of CD4 (+) T cells, exogenous proteins must be digested by endo/lysosomal enzymes in antigen-presenting cells (APC) to produce antigenic peptides that are able to be presented on class II molecules of the MHC. Studies described here inspect the functional significance of cathepsin L inhibition for antigen processing and T (h) 1/T (h) 2 differentiation in experimental leishmaniasis. We first demonstrated using in vitro systems that cathepsin L is one of the candidate endo/lysosomal enzymes in processing of soluble Leishmania antigen (SLA) and that its specific inhibitor, CLIK148, modulated the processing of SLA. BALB/c mice are known to be susceptible to infection with Leishmania major. Interestingly, treatment of BALB/c mice with CLIK148 exacerbated the infection by enhancing the development of SLA-specific T (h) 2-type response such as production of IL-4 and generation of T (h) 2-dependent specific IgE/IgG1 antibodies. Moreover, addition of CLIK148 in incubation of a SLA-specific CD4 (+) T cell line with APC up-regulated the production of IL-4. However, CLIK148 did not exert any direct influence on the function of T cells themselves. Taken together, these findings suggest that treatment of host mice with CLIK148 affects the processing of SLA in APC, resulting in the potentiation of T (h) 2-type immune responses and thus leading to exacerbation of the infection. Furthermore, endo/lysosomal cathepsin L was found to be functionally distinct from previously described cathepsins B and D.
Zhang
T
T
Department of Parasitology and Immunology, The University of Tokushima School of Medicine, 3 Kuramoto-cho, Tokushima 770-8503, Japan.
Maekawa
Y
Y
Sakai
T
T
Nakano
Y
Y
Ishii
K
K
Hisaeda
H
H
Dainichi
T
T
Asao
T
T
Katunuma
N
N
Himeno
K
K
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000953:Antigens, Protozoan / Q000276:immunology / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology; D011992:Endosomes / Q000201:enzymology; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007274:Injections, Intraperitoneal; D018320:Leishmania major / Q000187:drug effects* / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000201:enzymology* / Q000209:etiology / Q000276:immunology*; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D012995:Solubility; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; C400541:CA 074 methyl ester; C402823:CLIK 148; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D004852:Epoxy Compounds; D011725:Pyridines; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse