title: 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.
abstract: Tumor necrosis factor (TNF), like granulocyte-macrophage colony-stimul ating factor (GM-CSF), rapidly primed human monocytes for enhanced release of superoxide (O-2) stimulated by receptor-mediated agonists, N-formyl-methionyl-leucyl-phenylalanine (FMLP) and concanavalin A (Con A), but not by phorbol myristate acetate (PMA), which bypasses the receptors to stimulate the cells. The optimal priming was obtained by pretreatment 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 each cytokine alone. GM-CSF induced an increase in cytoplasmic pH but TNF did not. These findings suggest that TNF and GM-CSF activate monocytes 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 release of O-2 in human neutrophils. In additions, 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-receptor-mediated signaling pathways for triggering O-(2) release is active in neutrophils but inactive or defective in monocytes. TNF also enhanced phagocytosis of sialidase-treated autologous erythrocytes by monocytes, and this effect was further potentiated in the presence of autologous fresh serum. The significant enhancement of erythrophagocytosis was obtained at 1 U/mL TNF. At this concentration of TNF, the expression of C3bi-receptor (CD11b/CD18) was upregulated. These findings show that TNF rapidly primes human monocytes for enhanced release of O-(2) and erythrophagocytosis and suggest that TNF activates monocytes through autocrine or paracrine mechanisms at the inflammatory sites inasmuch as TNF is primarily produced by activated monocytes/macrophages.
authors.affiliation: Department of Cardiology, Jichi Medical School, Tochigi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kitagawa
authors.forename: A
authors.initials: A
authors.lastname: Yuo
authors.forename: M
authors.initials: M
authors.lastname: Yagisawa
authors.forename: E
authors.initials: E
authors.lastname: Azuma
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: J
authors.initials: J
authors.lastname: Masuyama
authors.forename: F
authors.initials: F
authors.lastname: Takaku
mesh_terms: D000328:Adult; D003179:Complement C3b / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D003593:Cytoplasm / Q000502:physiology; D004912:Erythrocytes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009000:Monocytes / Q000502:physiology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010587:Phagocytosis; D019000:Phosphotyrosine / Q000378:metabolism; D016028:Receptors, Leukocyte-Adhesion / Q000378:metabolism; D011994:Recombinant Proteins; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D016028:Receptors, Leukocyte-Adhesion; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D013481:Superoxides; D019000:Phosphotyrosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003179:Complement C3b; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate