Dysregulation of LDL receptor under the influence of inflammatory cytokines: A new pathway for foam cell formation 1 1See Editorial by van Zonneveld and Rabelink, p. 2037

Dysregulation of LDL receptor under the influence of inflammatory cytokines: A new pathway for foam cell formation. Lipid-mediated renal injury is an important component of glomerulosclerosis and its similarity to atherosclerosis is well described. This study focused on the relationship between lipid-mediated injury and inflammation by examining the role of inflammatory cytokines in the regulation of human mesangial cell low-density lipoprotein (LDL) receptors. A human mesangial cell line (HMCL) was used to study the effects of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) on the regulation of LDL receptor mRNA and protein in the presence of a high concentration of native LDL (250 μg/mL). Native LDL caused foam cell formation in HMCL in the presence of antioxidants, TNF-α and IL-1β. Both cytokines overrode LDL receptor suppression induced by a high concentration of LDL and increased LDL uptake by enhancing receptor expression. These cytokines also caused increased expression of SCAP [sterol responsive element binding protein (SREBP) cleavage activation protein], and an increase in the nuclear translocation of SREBP, which induces LDL receptor expression. These observations demonstrate that inflammatory cytokines can modify cholesterol-mediated LDL receptor regulation in mesangial cells, permitting unregulated intracellular accumulation of unmodified LDL and causing foam cell formation. These findings suggest that inflammatory cytokines contribute to lipid-mediated renal damage, and also may have wider implications for the study of inflammation in the atherosclerotic process.