Cytokine priming reduces dependence on TNF-R2 for TNF-alpha-mediated induction of macrophage nitric oxide generation.
In the presence of interferon-gamma (IFN-gamma), human tumor necrosis factor-alpha (Hu-TNF-alpha), which binds to murine TNF-alpha receptor type 1 (TNF-R1) but not to murine TNF-R2, was effective in inducing nitric oxide (NO) production in spleen-derived macrophages (M phi), albeit at concentrations 12.5-fold greater than those required by murine TNF-alpha (Mu-TNF-alpha), to achieve the same result. Addition of anti-TNF-R1 completely inhibited the Mu-TNF-alpha-mediated induction of NO, demonstrating that TNF-R1 is critical to the IFN-gamma-dependent TNF-alpha-mediated induction of M phi effector function. However, treatment with anti-TNF-R2 resulted in a partial inhibition of M phi activation. Spleen-derived M phi were more dependent on TNF-R2 than RAW 264.7 or peritoneal M phi based on their responsiveness to Hu-TNF-alpha. Priming of spleen-derived M phi with either IFN-gamma or granulocyte-macrophage colony-stimulating factor (GM-CSF) heightened the maximal responses to both TNF-alpha species and increased the overall effectiveness of Hu-TNF-alpha without increasing expression of either TNF-alpha receptor. The dependence of spleen-derived M phi on both TNF-alpha receptors for signaling the induction of effector function supports an active signaling role for TNF-R2 in its synergy with TNF-R1 rather than a passive ligand passing role.
Miller
A R
AR
Department of Microbiology, Quillen College of Medicine, East Tennessee State University, Johnson City, USA.
Suttles
J
J
Stout
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RD
D000818:Animals; D000937:Antigen-Antibody Reactions; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor