Enhancement of pulmonary natural killer cell activity by platelet activating factor. Mechanisms of activation involving Ca2+, protein kinase C, and lipooxygenase products.
The modulation of lung natural killer (NK) cell activity by platelet-activating factor (PAF) and the mechanisms underlying this regulation were examined. When rat lung large granular lymphocytes (LGL) were cultured with PAF we observed an elevation of NK cell activity in a concentration-dependent fashion. Peak effect was observed at 10(-9) M PAF. Kinetic studies indicated that this enhancement occurred when effector cells were preincubated with PAF for 18 h as well as for shorter times. Inhibition of protein synthesis by cycloheximide blocked the PAF-enhanced NK cell activity after preincubation for 18 h. Extracellular Ca2+ was also needed for the action of PAF as suggested by the effects of Ca2+ chelation with ethyleneglycol-bis-(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) and inhibition of Ca2+ entry into the cells with verapamil and diltiazem, all of which abrogated the action of PAF. Furthermore, the enhancement of cytotoxicity was blocked by specific PAF receptor antagonists BN 52021, BN 52111, and WEB 2086. The mechanism of activation appeared to involve protein kinase C (PKC) since pretreatment of lung LGL with the PKC inhibitors H-7 or staurosporine abrogated the PAF-induced effect. Inhibition of 5-lipoxygenase by AA-861 inhibited partially the PAF-induced augmentation of NK cell activity, suggesting an implication of endogenous leukotrienes (LT) in this system. In parallel, addition of exogenous LTB4 to lung LGL stimulated their NK cell activity but to a lower level comparatively with PAF. Taken together, our studies indicate that PAF can significantly augment lung NK cell activity and that this effect is dependent on PKC, 5-lipoxygenase, and extracellular calcium.
Thivierge
M
M
Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Canada.
Rola-Pleszczynski
M
M
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D002118:Calcium / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D007975:Leukotriene B4 / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D010972:Platelet Activating Factor / Q000276:immunology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains
D010972:Platelet Activating Factor; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D011493:Protein Kinase C; D002118:Calcium