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 c ould thereby influence the development of the plaque lesion, Cytokines , including TNF alpha, have been identified in human lesions, therefor e, we undertook a series of studies to evaluate the effect of TNF alph a on monocyte/macrophage apo E production, The addition of TNF alpha t o freshly isolated human monocytes led to a four- to fivefold increase of apo E mRNA abundance, The addition of TNF alpha to fully different iated macrophages either had no effect or modestly inhibited apo E mRN A expression, THP1 human monocytic cells also responded to TNF alpha i n a phenotype-specific manner, Treatment of these cells with TNF alpha produced a dose- and time-dependent increase in apo E mRNA, This incr ease was reflected in apo E synthesis and was associated with inhibiti on of DNA synthesis, and with induction of c-fos and ICAM-1 gene expre ssion, Cell-permanent analogues of ceramide did not reproduce TNF alph a effect on apo E, but antagonists of protein kinase C did inhibit its effect, TNF alpha induction of apo E mRNA abundance was associated wi th stimulation of apo E promoter-dependent gene transcription, In summ ary, TNF alpha stimulates apo E gene transcription, mRNA abundance, an d 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.