Induction of tumor necrosis factor alpha gene expression by lipoprotein lipase

In view of the suppressive effect of tumor necrosis factor alpha (TNF alpha) on lipoprotein lipase (LPL) and of the potential proatherogenic effects of these two macrophage secretory products, we have tested the possibility that LPL could modulate the production of TNF alpha. Treatment of macrophages with lipoprotein lipase induced tumor necrosis factor alpha gene expression and protein secretion. Maximal increase of TNF alpha mRNA levels occurred after a 3-h treatment with 200 ng/ml LPL. An additive effect of interferon gamma (IFN gamma) was observed on LPL-induced TNF alpha mRNA expression. De novo mRNA synthesis was required for induction of TNF alpha mRNA by LPL as no induction was observed when macrophages were pretreated with actinomycin D before adding LPL. We further established that LPL induced the transcription of the TNF alpha gene in macrophages. We also found that LPL caused the nuclear migration of one member of the NFkB family that appears to bind to a site in the murine TNF alpha gene promoter. Furthermore, we demonstrated that the treatment of macrophages with LPL increased the stability of TNF alpha mRNA. These results show that the TNF alpha gene induction in response to LPL involves both transcriptional activation and the enhancement of TNF alpha mRNA stability. Overall, our data demonstrate a new role for LPL, that of modulating macrophage TNF alpha gene expression. This effect may represent one of the mechanisms by which LPL may favor the development of atherosclerosis.