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The Cathepsin B Inhibitor, z-FA-FMK, Inhibits Human T Cell Proliferation In Vitro and Modulates Host Response to Pneumococcal Infection In Vivo¹

Clare P. Lawrence^*, Aras Kadioglu, Ai-Li Yang^*, William R. Coward^* and Sek C. Chow^2,*

^* Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom; and Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, United Kingdom

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- as well as the expression of IL-2R -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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Medical Research Council, United Kingdom.

² Address correspondence and reprint requests to Dr. Sek C. Chow, Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, University of Leicester, Leicester LE1 9HN, U.K.

³ Abbreviations used in this paper: z-FA-FMK, benzyloxycarbonyl-phenylalanine-alanine-fluoromethylketone; z-VAD-FMK, benzyloxycarbonyl-valine-alanine-Asp (OMe) fluoromethylketone; RA, rheumatoid arthritis, PI, propidium iodide; PARP, poly(ADP-ribose) polymerase.