TUMOR-NECROSIS-FACTOR-ALPHA MODULATES MONOCYTE/MACROPHAGE APOPROTEIN-E GENE-EXPRESSION

apo E has been shown to modulate cholesterol balance in arterial wall cells, Production of apo E by macrophages in atherosclerotic plaques could thereby influence the development of the plaque lesion, Cytokines, including TNF alpha, have been identified in human lesions, therefore, we undertook a series of studies to evaluate the effect of TNF alpha on monocyte/macrophage apo E production, The addition of TNF alpha to freshly isolated human monocytes led to a four- to fivefold increase of apo E mRNA abundance, The addition of TNF alpha to fully differentiated macrophages either had no effect or modestly inhibited apo E mRNA expression, THP1 human monocytic cells also responded to TNF alpha in a phenotype-specific manner, Treatment of these cells with TNF alpha produced a dose- and time-dependent increase in apo E mRNA, This increase was reflected in apo E synthesis and was associated with inhibition of DNA synthesis, and with induction of c-fos and ICAM-1 gene expression, Cell-permanent analogues of ceramide did not reproduce TNF alpha effect on apo E, but antagonists of protein kinase C did inhibit its effect, TNF alpha induction of apo E mRNA abundance was associated with stimulation of apo E promoter-dependent gene transcription, In summary, TNF alpha stimulates apo E gene transcription, mRNA abundance, and protein synthesis in the monocyte/macrophage in a phenotype-specific manner, Such regulation could significantly modify the amount of apo E present in vessel wall lesions.