Interferon-gamma enhances tumor necrosis factor-alpha production by inhibiting early phase interleukin-10 transcription.
The ability of cytokine synthesis inhibitory factor or interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) to modulate the production of tumor necrosis factor (TNF-alpha) induced by lipopolysaccharide (LPS) was examined in mouse bone marrow-derived macrophages (BMDM). IFN-gamma profoundly enhances LPS-stimulated TNF-alpha production, whereas IL-10 is markedly inhibitory, demonstrating the opposing effects of IFN-gamma and IL-10 on BMDM. Early neutralization of endogenously produced, LPS-stimulated IL-10 markedly enhanced short term TNF-alpha production, an effect further amplified by the absence of IFN-gamma priming. The regulatory effects of IFN-gamma and IL-10 apparently occurred at the translational (or post-translational) level, with TNF-alpha mRNA steady-state levels remaining unchanged. Furthermore, IFN-gamma exerts its enhancing effect on TNF synthesis by the transcriptional inhibition of IL-10. This in vitro finding was also confirmed in vivo. In the absence of LPS, IFN-gamma was not capable of inducing TNF-alpha production in BMDM, indicating that LPS or other signals are necessary for transcriptional activation. Reduced but significant TNF-alpha production in LPS-injected IFN-gamma receptor -/- mice suggests that IFN-gamma is not an absolute requirement and that other cytokines or cell types contribute in a secondary fashion to the priming of LPS-induced TNF-alpha production in vivo.
Shakhov
A N
AN
Institut fur Toxikologie, Eidgenossichen Technischen Hochschule, Schwerzenbach, Switzerland.
Woerly
G
G
Car
B D
BD
Ryffel
B
B
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma