title: Proteasome inhibitor and lymphocyte function: partial inhibition of cell-mediated cytotoxicity and implication that the lymphocyte proteasome may contain multiple chymotryptic domains.
abstract: The multicatalytic proteinase complex or proteasome possesses at least 4 distinct proteolytic activities. We have previously reported that the chymotrypsin-like activity of the rat natural killer cell proteasome may play a role in natural killer (NK) cell-mediated cytotoxicity or IL-2 activated NK (A-NK) cell-mediated cytotoxicity. Using a series of novel, Cephalon, Inc, synthetic proteasome inhibitors (CEP-1508, CEP-1612 and CEP-3117) which have been reported to be specific for the chymotrypsin-like activity of the proteasome, we have further investigated the possible role of the proteasome, with emphasis on the chymotryptic activity components, in cell-mediated cytotoxicity. We now report that these compounds can inhibit the rat NK proteasome in a dose dependent manner. Nevertheless, there is only a 50% inhibition of A-NK cell-mediated cytotoxicity. These results confirm and extend our previous results that the proteasome contributes, at least in part, to cell-mediated cytotoxicity. However, as anticipated, since multiple molecular pathways contribute to cell-mediated cytotoxicity, the proteasome contributes only partially to NK cell-mediated cytolytic reactivity. The exact role of the proteasome in NK cell-mediated killing, and whether single or multiple chymotryptic domains function directly or indirectly, remains to be fully determined.
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth 76107, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Kitson
authors.forename: M
authors.initials: M
authors.lastname: Lu
authors.forename: R
authors.initials: R
authors.lastname: Siman
authors.forename: R H
authors.initials: RH
authors.lastname: Goldfarb
mesh_terms: D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002918:Chymotrypsin / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism; D010797:Phthalimides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
chemical_list: C118003:CEP 1508; D004151:Dipeptides; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D010797:Phthalimides; C118004:CEP 1612; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex