Nicotinamide and 3-aminobenzamide interfere with receptor-mediated transmembrane signaling in murine cytotoxic T cells: independence of Golgi reorientation from calcium mobilization and inositol phosphate generation.
The two competitive inhibitors of ADP-ribosylation, nicotinamide and 3-aminobenzamide, have been reported to interfere with TNF-induced cell apoptosis, and there is evidence that they inhibit killer-induced target cell lysis as well. There are very few drugs known to specifically interfere with target apoptosis induced by killer cells. We therefore sought to explore the effects these inhibitors have on CTL-mediated cell lysis. Here we show that TcR-mediated transmembrane signaling in CTL, measured by Ca2+ mobilization and generation of inositol phosphates, is inhibited by nicotinamide. The possibility that all cell functions are suppressed by the drug is excluded by the finding that constitutive secretion of BLT serine esterase is not inhibited, whereas stimulated secretion of this enzyme is suppressed. We also show that nicotinamide does not interfere with CTL target cell binding or reorientation of the Golgi apparatus toward the target binding site. It is concluded that nicotinamide inhibits transmembrane signaling in CTL and thereby interferes with delivery of the lethal hit to targets.
Nowicki
M
M
Department of Microbiology, University of Southern California, Los Angeles 90033-0800.
Landon
C
C
Sugawara
S
S
Dennert
G
G
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006056:Golgi Apparatus / Q000648:ultrastructure; D053804:Granzymes; D007295:Inositol Phosphates / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008815:Mice, Inbred Strains; D009536:Niacinamide / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000502:physiology*
D001549:Benzamides; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D003208:Concanavalin A; D009536:Niacinamide; C025160:3-aminobenzamide; D053804:Granzymes; D012697:Serine Endopeptidases; D002118:Calcium