Tumor necrosis factor-α modulates monocyte/macrophage apoprotein E gene expression

Abstract

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 TNFα, have been identified in human lesions, therefore, we undertook a series of studies to evaluate the effect of TNFα on monocyte/macrophage apo E production. The addition of TNFα to freshly isolated human monocytes led to a four- to fivefold increase of apo E mRNA abundance. The addition of TNFα to fully differentiated macrophages either had no effect or modestly inhibited apo E mRNA expression. THP1 human monocytic cells also responded to TNFα in a phenotype-specific manner. Treatment of these cells with TNFα 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 TNFα effect on apo E, but antagonists of protein kinase C did inhibit its effect. TNFα induction of apo E mRNA abundance was associated with stimulation of apo E promoter- dependent gene transcription. In summary, TNFα 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.