Zymosan-stimulated tumor necrosis factor-alpha production by human monocytes. Down-modulation by phorbol ester.
In this study, we showed that human monocytes produced TNF-alpha in response to zymosan, a particulate agonist. Protein kinase C (PKC) seems to play a regulatory role in zymosan-induced TNF-alpha secretion. The pretreatment of monocytes with PMA induced a dose-dependent inhibition of zymosan-stimulated TNF production. This inhibition was likely due to an activation of PKC because it was prevented by inhibitors of PKC, sphingosine, and staurosporine. Moreover, PMA elicited a profound down-modulation of zymosan binding to monocytes. The inhibition of zymosan binding and TNF production displayed similar dose-dependence, suggesting that both events were closely related. In addition, PMA did not modify the expression of CD11b/CD18 receptor that is involved in zymosan recognition. In view of these findings, qualitative changes of CD11b/CD18 molecules might account for the inhibition of zymosan binding and TNF production. Thus, PMA specifically increased the association of CD11b/CD18 with the detergent-insoluble cytoskeleton. Cytochalasin B but not microtubule disrupters, nocodazole and colchicine, partially prevented the inhibition of zymosan binding. Hence, the inhibitory action of PMA on zymosan binding seems to be mediated by an increase in attachment of zymosan receptor to cytoskeleton and more likely to microfilaments. The regulatory activity of PKC might represent a first way of limiting cytokine over-production in response to pathogens which interact with monocytes via CD11/CD18 molecules.
Laboratoire d'Immunologie, Hôpital de Sainte-Marguerite, Marseille, France.
M V
MV
Sanguedolce
C
C
Capo
P
P
Bongrand
J L
JL
Mege
D015703:Antigens, CD / Q000032:analysis; D018845:CD11 Antigens; D018821:CD18 Antigens; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D016177:Macrophage-1 Antigen / Q000502:physiology; D009000:Monocytes / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015054:Zymosan / Q000494:pharmacology*
D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate