Original Article

Isolation of macrophage-like cell mutants resistant to the cytotoxic effect of oxidized low density lipoprotein

Correspondence to: Seikoh Horiuchi.

A high concentration of oxidized low density lipoprotein (Ox-LDL) showed a cytotoxic effect on mouse macrophage-derived J774 cells. Mutant cells were selected from these cells that were resistant to the cytotoxic effect of Ox-LDL. One mutant form, named JO21b cells, was characterized in the present study. In spite of a marked resistance to the cytotoxic effect of Ox-LDL, JO21b cells were apparently as sensitive as the parent cells not only to toxic moieties of Ox-LDL, such as 7-ketocholesterol and lysophosphatidylcholine, but also to t-butyl hydroperoxide, an artificial lipid hydroperoxide analog. However, the cellular association of ¹²⁵I-labeled Ox-LDL with, and subsequent endocytic degradation by JO21b cells was reduced by 70–80% compared with J774 cells. Similarly, accumulation of cholesteryl esters in JO21b cell by Ox-LDL was also reduced by 70%. Northern blot analyses of type I and type II macrophage scavenger receptors (type I and type II MSR) demonstrated that the mRNA levels of JO21b cells were lower than those of J774 cells. Moreover, peritoneal macrophages obtained from MSR-knockout mice showed a higher resistance to the cytotoxic effect of Ox-LDL than those from their wild-type littermates.

Our results suggest, therefore, that macrophage scavenger receptor-mediated endocytic uptake of oxidized low density lipoproteins (Ox-LDL) may play an enhancing role in Ox-LDL cytotoxicity to macrophages or macrophage-derived cells.—Hakamata, H., A. Miyazaki, M. Sakai, H. Matsuda, H. Suzuki, T. Kodama, and S. Horiuchi. Isolation of macrophage-like cell mutants resistant to the cytotoxic effect of oxidized low density lipoproteins. J. Lipid Res. 1998. 39: 482–494.

Supplementary key words: oxidized low density lipoprotein, macrophage, somatic cell mutant, cytotoxicity, macrophage scavenger receptors, atherosclerosis

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