Interferon gamma drastically modifies the regulation of interleukin 1 genes by endotoxin in U937 cells

The Journal of Clinical Investigation
C UclaB Mach

Abstract

IL-1 alpha, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) gene expression is induced by LPS (endotoxin) in monocytes/macrophages and in some monocytic cell lines. IFN gamma and 1 alpha,25-dihydroxyvitamin D3 (1,25[OH]2D3) are important macrophage-activating factors. They induce changes in the human monocyte cell line U937 that reflect cellular differentiation. We have studied the effect of IFN-gamma and of 1,25(OH)2D3 on the expression of IL-1 and TNF-alpha messenger RNA in response to LPS. The induction of these genes by LPS is immediate and transient, with a maximum in 3 h. Preincubation of the cells with IFN-gamma or with 1,25(OH)2D3 increases these mRNA responses to LPS about fourfold. More importantly, cells exposed to IFN-gamma for 72 h exhibit a drastically different and unexpected pattern of IL-1 alpha and IL-1 beta gene response to LPS. Instead of the normal transient response, one then observes a sustained increase in IL-1 alpha and IL-1 beta gene expression over at least 16 h after LPS stimulation. This was measured both at the level of mRNA and by direct transcription assays (run-off). This striking effect of IFN-gamma on the kinetics of IL-1 gene response does not apply to the TNF-alpha gene. Interestingly...Continue Reading

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