IL-6 triggers lysosomal degradation of LDL-R and enhances LDL-C uptake in vascular endothelial cells via macropinocytosis

Journal article

Background: Endothelial dysfunction profoundly compromises the barrier function that precludes trans-endothelial entry of low-density lipoprotein cholesterol (LDL-C) into the vessel wall. LDL-C retention in the vessel wall is atherogenic and its flux involves several mechanisms including LDL-receptor (LDL-R) mediated transcytosis, a process that is facilitated by inflammatory stressors. In this study, we aimed to investigate the role of interleukin-6 (IL-6) in regulating LDL-R and LDL-C uptake by vascular endothelial cells. Method: We used commercially available Human umbilical vein endothelial cells (HUVECs) in this study. Flow cytometry, western blotting, qRT-PCR and ELISA were used to investigate expression of LDL-R and Mylip/IDOL. LDL-C uptake and free cholesterol levels in HUVECs was assessed using flowcytometry and mass-spectrometry respectively. Results: We show that HUVECs treated with a combination of IL-6 and soluble IL-6 receptor (sIL-6R) result in a significant reduction in surface expression of LDL-R, an effect that is reversed by soluble gp130Fc – an antagonist of IL-6 trans-singling. Using pharmacological inhibitors and gene silencing techniques, we demonstrate that IL-6 trans-signaling induced downregulation of LDL-R is attained through lysosomal degradation mediated by the E3 ubiquitin ligase Mylip. Conversely, HUVECs treated with IL-6 in combination with sIL-6R exhibit markedly increased uptake of native LDL-C which is also inhibited by sgp130Fc, the actin inhibitor Cytochalasin D and the macropinocytosis inhibitor EIPA. Although stimulation of HUVECs upregulated the expression of scavenger receptors CD36 and CXCL16, their contribution to native LDL-C uptake turned out to be negligible. Conclusion: Collectively, this study highlights the role of IL-6 in the regulation of LDL-R expression and cholesterol homeostasis in vascular ECs. IL-6 trans-signaling downregulates LDL-R yet increases LDL-C uptake via an LDL-R–independent, actin-dependent macropinocytosis pathway.

Authors: Zegeye, MM; Veettil, JT; Paramel, GV; Kurt, S; Salihovic, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Molecular Medicine
• Volume: 32
• Issue: 1
• Article number: 65
• Publication date: 2026-04-25
• Acceptance date: 2026-04-12
• DOI: 10.1186/s10020-026-01484-7
• EISSN: 1528-3658
• ISSN: 1076-1551
• Language: English
• Keywords: Macropinocytosis; Trans-signaling; Endothelial dysfunction; Atherosclerosis; Mylip/IDOL