Gamma interferon and lipopolysaccharide interact at the level of transcription to induce tumor necrosis factor alpha expression.
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.
Lee
J Y
JY
Division of Immunologic and Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Sullivan
K E
KE
D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2; D008070:Lipopolysaccharides / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020032:Tyrphostins / Q000494:pharmacology
D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2