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

CD36 is 1 of the class B scavenger receptor expressed on monocytes, monocyt e-derived macrophages (M phi), platelets, and adipocytes. In our previous s tudies, we reported that the uptake of oxidized low density lipoproteins (O xLDLs) is reduced by approximate to 50% in M phi from CD36-deficient patien ts compared with that in control subjects. Recently, we have shown that CD3 6 is highly expressed in human atherosclerotic aorta. Possibilities have be en raised that besides the wide distribution and multifunctional characteri stics of CD36, this molecule may also be involved in the mediation of intra cellular signaling. The aim of the present study was to elucidate the role of CD36 in cytokine secretion and to investigate the CD36-mediated intracel lular signaling stimulated by OxLDL. On addition of OxLDL or thrombospondin -1, the M phi from CD36-deficient patients secreted significantly less amou nts of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) compared with those from controls. RNase protection assay with multi probe template sets demonstrated that after incubation with OxLDL, the mRNA s of a variety of cytokines, including genes encoding IL-1Ra, IL-1 beta, IL -6, TNF-alpha and -beta, and interferon (IFN)-gamma and -beta, were signifi cantly lower in the M phi of patients. The addition of antibody against CD3 6 attenuated this OxLDL-induced response in controls. We also observed a re duced response in nuclear factor-kappa B (NF-kappa B) activity in OxLDL-sti mulated M phi from CD36-deficient patients. Unlike OxLDL, stimulation by li popolysaccharide induced an increase in NF-kappa B activity in M phi from C D36-deficient patients, suggesting that lipopolysaccharide-mediated signali ng 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-kappa B activation and subse quent cytokine expression.