Tumor necrosis factor-alpha and interleukin-1 alpha synergistically enhance phorbol myristate acetate-induced superoxide production by rat bone marrow-derived macrophages.
Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) are secreted by macrophages in response to endotoxin challenge. In addition, macrophages express receptors for both of these cytokines. Macrophage function can therefore be modulated by regulation of both cytokine production and receptor levels. We have initiated studies to investigate the effects of TNF-alpha and IL-1 alpha on macrophage function. Macrophages were obtained by in vitro differentiation of rat bone marrow cells. The biologic response to TNF-alpha and IL-1 alpha was assessed by measurement of superoxide production quantitated by the reduction of cytochrome c in response to phorbol myristate acetate. Macrophages were treated with endotoxin (LPS), TNF-alpha, and IL-1 alpha, alone and in combination. None of these agents was a primary stimulus for superoxide production. However, after treatment with endotoxin or TNF-alpha for 24 h, macrophages were primed for enhanced production of superoxide. The priming effect of LPS was due, at least in part, to endogenously produced TNF-alpha, since anti-murine TNF-alpha antibodies blocked the LPS-mediated priming by approximately 30%. IL-1 alpha did not prime macrophages, but treatment with IL-1 alpha followed by TNF-alpha or LPS resulted in enhanced superoxide production. IL-1 alpha treatment of macrophages resulted in an increase in TNF-alpha receptors, which might explain the synergistic priming of TNF-alpha and IL-1 alpha.
Tanner
W G
WG
Department of Veterans Affairs, Vanderbilt University, Nashville, Tennessee.
Welborn
M B
MB
Shepherd
V L
VL
D000818:Animals; D000906:Antibodies; D001853:Bone Marrow / Q000378:metabolism*; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004357:Drug Synergism; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
D000906:Antibodies; D003574:Cytochrome c Group; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D013755:Tetradecanoylphorbol Acetate