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(Circulation. 2001;103:1142.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Evidence of Macrophage Foam Cell Formation by Very Low-Density Lipoprotein Receptor

Interferon- Inhibition of Very Low-Density Lipoprotein Receptor Expression and Foam Cell Formation in Macrophages

Shotaro Kosaka, MD; Sadao Takahashi, MD, PhD; Katsuhiko Masamura, MD; Hideo Kanehara, MD; Juro Sakai, MD, PhD; Gen Tohda, MD, PhD; Eiko Okada, MD, PhD; Koji Oida, MD, PhD; Tadao Iwasaki, MS; Hiroaki Hattori, PhD; Tatsuhiko Kodama, MD, PhD; Tokuo Yamamoto, PhD; Isamu Miyamori, MD, PhD

From the Third Department of Internal Medicine (S.K., S.T., K.M., H.K., G.T., E.O., K.O., I.M.), Fukui Medical University, Fukui, Japan; Second Department of Internal Medicine (J.S.), Tohoku University School of Medicine, Sendai, Japan; Research Department (T.I., H.H.), R & D Center, BML, Inc, Kawagoe, Japan; Department of Molecular Biology and Medicine (T.K.), Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan; and Tohoku University Gene Research Center (T.Y.), Sendai, Japan.

Correspondence to Sadao Takahashi, MD, PhD, the Third Department of Internal Medicine, Faculty of Medicine, Fukui Medical University, Matsuoka-cho, Fukui, Japan. E-mail sadaost{at}fmsrsa.fukui-med.ac.jp

Background—Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)- on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages.

Methods and Results—THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN- was added to the medium, and expression of the VLDL receptor was determined. ¹²⁵I-ß-VLDL degradation study and oil red O staining were examined. In THP-1 macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN- inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN- receptor mRNA increased during differentiation to macrophages. ¹²⁵I-ß-VLDL degradation study and oil red O staining showed that IFN- significantly inhibited foam cell formation after the uptake of ß-VLDL. LDL receptor–related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages, IFN- also inhibited VLDL receptor expression and foam cell formation by ß-VLDL.

Conclusions—VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN- inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway.

Key Words: lipoproteins • interferon- • cells • receptors • proteins

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