ACTIVATION OF HUMAN MONOCYTE FUNCTIONS BY TUMOR-NECROSIS-FACTOR - RAPID PRIMING FOR ENHANCED RELEASE OF SUPEROXIDE AND ERYTHROPHAGOCYTOSIS,BUT NO DIRECT TRIGGERING OF SUPEROXIDE RELEASE

Tumor necrosis factor (TNF), like granulocyte-macrophage colony-stimul ating factor (GM-CSF), rapidly primed human monocytes for enhanced rel ease of superoxide (O-2(-)) stimulated by receptor-mediated agonists, N-formyl-methionyl-leucylphenylalanine (FMLP) and concanavalin A (Con A), but not by phorbol myristate acetate (PMA), which bypasses the rec eptors to stimulate the cells. The optimal priming was obtained by pre treatment of suspended monocytes with 10 U/mL TNF for 10 minutes at 37 degrees C. The potency of the maximal priming effect was TNF > GM-CSF , and the combined effect of TNF and GM-CSF was greater than that of e ach cytokine alone. GM-CSF induced an increase in cytoplasmic pH, but TNF did not. These findings suggest that TNF and GM-CSF activate monoc ytes through different mechanisms. TNF and GM-CSF by themselves never triggered O-2(-) release in suspended monocytes or monocytes adherent to endothelial cells, although both cytokines triggered massive releas e of O-2(-) in human neutrophils. In addition, TNF and GM-CSF induced tyrosine phosphorylation of a 42-kD protein in neutrophils but not in monocytes. These findings suggest that the TNF-receptor- or GM-CSF-rec eptor-mediated signaling pathway for triggering O-2(-) release is acti ve in neutrophils but inactive or defective in monocytes. TNF also enh anced phagocytosis of sialidase-treated autologous erythrocytes by mon ocytes, and this effect was further potentiated in the presence of aut ologous fresh serum. The significant enhancement of erythrophagocytosi s was obtained at 1 U/mL TNF. At this concentration of TNF, the expres sion of C3bi-receptor (CD11b/CD18) was upregulated. These findings sho w that TNF rapidly primes human monocytes for enhanced release of O-2( -) and erythrophagocytosis and suggest that TNF activates monocytes th rough autocrine or paracrine mechanisms at the inflammatory sites inas much as TNF is primarily produced by activated monocytes/macrophages.