The cathepsin B inhibitor, z-FA-FMK, inhibits human T cell proliferation in vitro and modulates host response to pneumococcal infection in vivo.
The cathepsin B inhibitor, benzyloxycarbonyl-phenyl-alanyl-fluoromethylketone (z-FA-FMK) at nontoxic doses was found to be immunosuppressive and repressed human T cell proliferation induced by mitogens and IL-2 in vitro. We showed that z-FA-FMK suppresses the secretion of IL-2 and IFN-gamma as well as the expression of IL-2R alpha-chain (CD25) in activated T cells, whereas the expression of the early activated T cell marker, CD69, was unaffected. Furthermore, z-FA-FMK blocks NF-kappaB activation, inhibits T cell blast formation, and prevents cells from entering and leaving the cell cycle. z-FA-FMK inhibits the processing of caspase-8 and caspase-3 to their respective subunits in resting T cells stimulated through the Ag receptor, but has no effect on the activation of these caspases during Fas-induced apoptosis in proliferating T cells. When administered in vivo, z-FA-FMK significantly increased pneumococcal growth in both lungs and blood, compared with controls, in a mouse model of intranasal pneumococcal infection. Because host response to bronchopneumonia in mice is T cell dependent, our collective results demonstrated that z-FA-FMK is immunosuppressive in vitro and in vivo.
Lawrence
Clare P
CP
Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom.
Kadioglu
Aras
A
Yang
Ai-Li
AL
Coward
William R
WR
Chow
Sek C
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007659:Ketones / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D011008:Pneumococcal Infections / Q000201:enzymology / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007659:Ketones; C057383:MDL 201053; D002401:Cathepsin B