Dysregulation of LDL receptor under the influence of inflammatory cytokines: A new pathway for foam cell formation

Background. Lipid-mediated renal injury is an important component of glomer ulosclerosis and its similarity to atherosclerosis is well described. This study focused on the relationship between lipid-mediated injury and inflamm ation by examining the role of inflammatory cytokines in the regulation of human mesangial cell low-density lipoprotein (LDL) receptors. Methods. A human mesangial cell line (HMCL) was used to study the effects o f tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta ) on the regulation of LDL receptor mRNA and protein in the presence of a h igh concentration of native LDL (250 mug/mL). Results. Native LDL caused foam cell formation in HMCL in the presence of a ntioxidants, TNF-alpha and IL-1 beta. 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 ex pression of SCAP [sterol responsive element binding protein (SREBP) cleavag e activation protein], and an increase in the nuclear translocation of SREB P, which induces LDL receptor expression. Conclusion. These observations demonstrate that inflammatory cytokines can modify cholesterol-mediated LDL receptor regulation in mesangial cells, per mitting unregulated intracellular accumulation of unmodified LDL and causin g foam cell formation. These findings suggest that inflammatory cytokines c ontribute to lipid-mediated renal damage, and also may have wider implicati ons for the study of inflammation in the atherosclerotic process.