Oxidized LDL-induced NF-κB activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients

Abstract

CD36 is 1 of the class B scavenger receptor expressed on monocytes, monocyte-derived macrophages (Mφ), platelets, and adipocytes. In our previous studies, we reported that the uptake of oxidized low density lipoproteins (OxLDLs) is reduced by ≃50% in Mφ from CD36-deficient patients compared with that in control subjects. Recently, we have shown that CD36 is highly expressed in human atherosclerotic aorta. Possibilities have been raised that besides the wide distribution and multifunctional Characteristics of CD36, this molecule may also be involved in the mediation of intracellular signaling. The aim of the present study was to elucidate the role of CD36 in cytokine secretion and to investigate the CD36-mediated intracellular signaling stimulated by OxLDL. On addition of OxLDL or thrombospondin-1, the Mφ from CD36-deficient patients secreted significantly less amounts of tumor necrosis factor-a (TNF-α) and interleukin-1β (IL-1β) compared with those from controls. RNase protection assay with multiprobe template sets demonstrated that after incubation with OxLDL, the mRNAs of a variety of cytokines, including genes encoding IL-1Ra, IL-1β, IL-6, TNF-α and -β, and interferon (IFN)-γ and -β, were significantly lower in the Mφ of patients. The addition of antibody against CD36 attenuated this OxLDL-induced response in controls. We also observed a reduced response in nuclear factor-κB (NF-κB) activity in OxLDL-stimulated Mφ from CD36-deficient patients. Unlike OxLDL, stimulation by lipopolysaccharide induced an increase in NF-κB activity in Mφ from CD36-deficient patients, suggesting that lipopolysaccharide-mediated signaling was conserved. These results demonstrate that in addition to the reduced OxLDL uptake that we reported previously, CD36-deficient patients may also have an impaired response of OxLDL-induced NF-κB activation and subsequent cytokine expression.