Tumor Necrosis Factor- et 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 develop-ment of the plaque lesion. Cytokines, including TNFa, have been identified in human lesions, therefore, we undertook a series of studies to evaluate the effect ofTNFa on monocyte/ macrophage apo E production. The addition of TNFa to freshly isolated human monocytes led to a four- to fivefold increase of apo E mRNA abundance. The addition of TNFa to fully differentiated macrophages either had no effect or modestly inhibited apo E mRNA expression. THP1 human monocytic cells also responded to TNFa in a phenotype-specific manner. Treatment of these cells with TNFx pro-duced a dose- and time-dependent increase in apo E mRNA. This increase was reflected in apo E synthesis and was asso-ciated with inhibition of DNA synthesis, and with induction of c-fos and ICAM-1 gene expression. Cell-permanent ana-logues of ceramide did not reproduce TNFa effect on apo E, but antagonists of protein kinase C did inhibit its effect. TNFa induction of apo E mRNA abundance was associated with stimulation of apo E promoter-dependent gene tran-scription. In summary, TNFa stimulates apo E gene tran-scription, 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. (J. Clin. Invest. 1995. 96:915-922.) Key words: cytokines * atherosclerosis * mac-rophage activation * protein kinase C * ceramid