SPONTANEOUS PROGRAMMED CELL-DEATH (PCD) PROCESS OF LYMPHOCYTES OF FIV-INFECTED CATS - PHARMACOLOGICAL MODULATION IN-VITRO

We previously reported that unstimulated lymphocytes in culture from F IV-infected cats undergo spontaneous apoptosis in vitro as indicated b y internucleosomal DNA fragmentation and hypodiploid DNA content of nu clei. Unlike what is reported in HIV-infected individuals, we observed that cell death of cat lymphocytes was inhibited by activation. Spont aneous apoptosis was reduced by the addition of cat serum, interleukin s [interleukin (IL)1, IL2, IL6 and interferon-gamma (IFN gamma)] and a fter activation by phorbol ester [phorbol myristyl acetate (PMA)], sup erantigens [staphylococcal enterotoxin B (SEB), staphylococcal enterot oxin A (SEA)], and to a lesser extent by mitogens such as Concanavalin A and pokeweed mitogen. In contrast, apoptosis of lymphocytes from FI V-infected, but not from control cats was increased in the presence of calcium ionophore (ionomycin). In this study, we studied the spontane ous programmed cell death (PCD)-inducing pathways, and the mechanisms of action of PMA, SEB and SEA. Spontaneous lymphocyte apoptosis of FIV -infected cats was inhibited by cycloheximide, ZnSO4 and N-acetyl-cyst ein. The preventive effect of PMA was abolished by inhibitors of kinas es (staurosporine, H7, genistein) and partially by actinomycin. The pr eventive effect of SEB and SEA was inhibited by actinomycin, but not b y inhibitors of kinases. Calyculin, an inhibitor of phosphatase, had n o effect either on spontaneous apoptosis, or on the action of PMA, SEB and SEA. Ionomycin-induced apoptosis was found sensitive to PMA and c ytokines. In FIV-infected cats, these data suggest that the mature lym phocytes appear programmed to die by apoptosis, unless rescued by spec ific agents, such as protein kinase C activators or growth factors, an d that spontaneous PCD seems to be dependent on de novo protein synthe sis (see the effect of cycloheximide). The effects of PMA, SEB and SEA are probably mediated by de novo proteins which, for PMA, undergo a p hosphorylation involving serine-threonineand/or tyrosine groups. Our d ata suggest a clear difference between lymphocytes from FIV-infected c ats and lymphocytes from HIV-infected humans, with regard to their met abolic regulation. (C) 1997 International Society for Immunopharmacolo gy.