Gamma Interferon and Lipopolysaccharide Interact at the Level of Transcription To Induce Tumor Necrosis Factor Alpha Expression

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Abstract
Lipopolysaccharide (LPS) is a very potent inducer of tumor necrosis factor alpha (TNF-alpha) expression from monocytes and macrophages. Another inflammatory cytokine, gamma interferon (IFN-gamma), can potentiate the effects of LPS, but the mechanism is not thoroughly understood. Previous reports emphasized the ability of IFN-gamma to upregulate CD14 expression (the receptor for LPS), and nearly all studies have utilized sequential stimulation with IFN-gamma followed by LPS to exploit this phenomenon. This study demonstrates that IFN-gamma can upregulate the effect of LPS at the level of transcription. Human monoblastic Mono-Mac-6 cells produced up to threefold-greater levels of TNF-alpha when simultaneously stimulated with LPS and IFN-gamma compared to treatment with LPS alone. RNase protection studies showed a similar increase in RNA beginning as early as within 30 min. The synthesis of TNF-alpha mRNA in IFN-gamma- and LPS-treated Mono-Mac-6 cells was also temporally prolonged even though the message turnover rate was identical to that seen in LPS stimulated cells. The modulatory effect of IFN-gamma may be mediated by Jak2.