Mechanisms of differential regulation of interleukin‐6 mRNA accumulation by tumor necrosis factor alpha and lymphotoxin during monocytic differentiation

Abstract

In the present report we compare the capacity of two related cytokines, tumor necrosis factor (TNF) alpha and lymphotoxin (LT), to modulate mRNA levels of interleukin-6 (IL-6) in cells representing different stages of monocytic differentiation including the human leukemia cell lines HL 60, U 937, THP-1, MonoMac l and peripheral blood monocytes. We show that the capacity of TNF alpha and LT to induce IL-6 mRNA accumulation increases as monocytic differentiation proceeds with TNF alpha being more potent than LT, suggesting that alternate pathways may be used by differentiating cells to control expression of IL-6. In contrast, in monocytes which constitutively synthesize IL-6 transcripts, TNF alpha and LT treatment had opposite effects on levels of IL-6 mRNA accumulation. In these cells TNF alpha enhanced steady state levels of IL-6 transcripts due to mRNA stabilization, whereas LT shortened IL-6 mRNA half-life, most likely due to induction of a RNA destabilizer since LT-mediated downregulation of levels of IL-6 mRNA in monocytes could be prevented by inhibition of protein synthesis. Neither TNF alpha nor LT altered IL-6 mRNA accumulation by interfering with preexisting transcription factors since both TNF alpha and LT required de novo protein synthesis to exert their effects.

Cytokine gene expression in human peripheral blood mononuclear cells stimulated by mannoprotein constituents from Candida albicans

“…In particular, IFN--y mRNA was substantially elevated in CHX-treated PBMC either unstimulated or stimulated with IL-2 or MP. In the second pattern, CHX inhibited the accumulation of PPDinduced IL-2 mRNA and MP-induced GM-CSF mRNA while having variable effects on the expression of IL-6 mRNA, in agreement with previous reports (1,9,41). MP-induced IL-6 mRNA expression was inhibited by CHX in the samples from the donor used for the experiment reported in Fig.…”

Leukotriene B4 transcriptionally activates interleukin‐6 expression involving NK‐xB and NF‐IL6

“…IL-6 mRNA in LTBl-treated monocytes accumulated for a period of up to 15 h. Taking into account the short half-life of IL-6 mRNA of approx. 30 min in monocytes [34], the prolonged expression of IL-6 mRNA in LTB4-treated cells can not be explained solely by the relatively transient increase in the transcriptional rate of this gene. These findings rather suggest that additional, e.g.…”

Interleukin-6 and renal cell cancer: Production, regulation, and growth effects

“…Alternatively, IFN7 may have independent actions on IL-6 mRNA accumulation, as we found that IFNy alone enhanced IL-6 gene expression 12 h after stimulation in two of the five tumor lines (R4, R6). These cytokines may themselves act as or induce other protein factors to act as short-lived activators of gene expression or alter mRNA stability [5]. Regardless of the speculative mechanism involved, the regulation of IL-6 production in RCC by cytokines is consistent with observations made in other cell types.…”

“…TNFc~ has been shown to be a stimulator of IL-6 production in a number of cell types [7,9,13,21,22,26,38,40,41]. It was found to have stimulatory effects on IL-6 mRNA transcript synthesis [5] and has been shown consistently to increase the stability of IL-6 mRNA [33]. It was also demonstrated that TNFc~, when administered to cancer patients, could induce considerable amounts of IL-6 protein in plasma [7].…”