THE EFFECTS OF OXIDIZED LOW-DENSITY LIPOPROTEINS ON INDUCIBLE MOUSE MACROPHAGE GENE-EXPRESSION ARE GENE AND STIMULUS-DEPENDENT

Oxidized LDL has been previously reported to suppress the expression o f genes induced in mononuclear phagocytes by inflammatory stimuli. In this study we extend these Endings to demonstrate that the suppressive effects of oxidized LDL vary depending upon the gene being monitored and the stimulus being used to induce or enhance its expression. The e xpression of a selection of LPS-inducible genes exhibited differential sensitivity to pretreatment with oxidized LDL, Furthermore, the abili ty of oxidized LDL to suppress gene expression varied markedly with th e inducing stimulus used. TNF alpha and IP-10 mRNA expression induced by IFN gamma and IL-2 was markedly more sensitive to suppression by ox idized LDL than that induced by LPS, The cooperative effects of TFN ga mma and LPS on the expression of the inducible nitric oxide synthase g ene were suppressed by oxidized LDL while the antagonistic effect of I FN gamma on LPS-induced expression of the TNF receptor type II mRNA wa s not altered. The suppressive activity of LDL was acquired only after extensive oxidation and was localized in the extractable lipid compon ent. These results suggest a potent and direct connection between the oxidative modification of LDL and the chronic inflammation seen in ath erogenic lesions. Furthermore, the appreciable selectivity of oxidized LDL in mediating secondary control of cytokine gene expression demons trates that the active material(s) is targeted to disrupt specific int racellular signaling pathways.