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 1 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.