Specific cathepsin B inhibitor is cell-permeable and activates presentation of TTC in primary human dendritic cells.
Cathepsins of the cysteine, aspartyl, and serine classes are involved in antigen processing in the class II major histocompatibility complex (MHC) loading compartment. Investigation of these proteases in living cells is difficult to perform due to the lack of highly specific cell-permeable inhibitors. Recently, a highly selective cathepsin B (CatB) inhibitor, Z-Arg-Leu-Arg-alpha-aza-glycyl-Ile-Val-OMe (ZRLR), was described. We found that ZRLR is cell-permeable and specifically inhibits CatB, in contrast to the CatB inhibitor, CA074-OMe, which blocks cysteine cathepsins in addition to CatB in primary human antigen-presenting cells (APC). Furthermore, we compared both CA074-OMe and ZRLR in the ability to alter tetanus toxin C-fragment (TTC) presentation to T cells by different APC. As a result, we found enhanced presentation of TTC in the presence of ZRLR, as determined by detection of pro-inflammatory cytokines. We conclude that ZRLR is a specific, cell-permeable CatB inhibitor which can be used for antigen presenting studies in situ.
Catheomics, Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
Michael
M
Reich
Ewa
E
Wieczerzak
Elzbieta
E
Jankowska
David
D
Palesch
Bernhard O
BO
Boehm
Timo
T
Burster
D017951:Antigen Presentation / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002463:Cell Membrane Permeability; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013744:Tetanus Toxin / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology
C400541:CA 074 methyl ester; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D020381:Interleukin-17; D009842:Oligopeptides; D010446:Peptide Fragments; D013744:Tetanus Toxin; D014409:Tumor Necrosis Factor-alpha; C542812:benzyloxycarbonyl-arginyl-leucyl-arginyl-alpha-azaglycyl-isoleucyl-valine methyl ester; C040635:tetanus toxin fragment C; D007371:Interferon-gamma; D002401:Cathepsin B