Tumor necrosis factor as an activator of human granulocytes. Potentiation of the metabolisms triggered by the Ca2+-mobilizing agonists.
TNF stimulated superoxide (O2-) release directly in human granulocytes in a dose-dependent manner (1 to 1000 U/ml), although its potency was weak. TNF-induced O2- release was inhibited by cAMP agonists or ionomycin, and was not accompanied with an increase in cytoplasmic free Ca2+ [( Ca2+]i) and membrane potential changes (depolarization). These findings indicate that neither Ca2+ mobilization nor membrane depolarization is required for TNF-receptor-mediated cell activation. The pretreatment of human granulocytes with TNF enhanced O2- release and membrane depolarization in parallel stimulated by the receptor-mediated Ca2+-mobilizing agonists (FMLP, Con A, and wheat germ agglutinin) or the Ca2+ ionophore ionomycin, but not by PMA, a direct activator of protein kinase C. The optimal effect was obtained by pretreatment of cells with 100 U/ml TNF for 5 to 10 min at 37 degrees C, although the magnitude of enhancement varied according to the agonists used as subsequent stimuli. TNF did not affect an increase in [Ca2+]i stimulated by the Ca2+-mobilizing agonists, except Con A. Con A-induced increase in [Ca2+]i was enhanced by TNF in a dose-dependent manner. These diverse effects of TNF could be partly explained by the exclusive potentiation by TNF of the metabolic events triggered by an increase in [Ca2+]i.
Yuo
A
A
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Kitagawa
S
S
Suzuki
I
I
Urabe
A
A
Okabe
T
T
Saito
M
M
Takaku
F
F
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D003208:Concanavalin A / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004987:Ethers / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015759:Ionomycin; D007476:Ionophores / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014909:Wheat Germ Agglutinins / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D002120:Calcium Channel Agonists; D004987:Ethers; D007476:Ionophores; D014409:Tumor Necrosis Factor-alpha; D014909:Wheat Germ Agglutinins; D003208:Concanavalin A; D015759:Ionomycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen