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      Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE).

      The Journal of Biological Chemistry
      ADAM Proteins, Acetophenones, pharmacology, Alternative Splicing, Amyloid Precursor Protein Secretases, Animals, Benzopyrans, Blotting, Western, COS Cells, Cell Line, Cell Membrane, metabolism, Ceramides, Cholesterol, Cyclodextrins, Dimerization, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Fibroblasts, Humans, Interleukin-6, Lipid Metabolism, Membrane Proteins, Metalloendopeptidases, Mice, Mice, Transgenic, Monocytes, Precipitin Tests, Protein Kinase C, Protein Structure, Tertiary, Receptors, Interleukin-6, Sphingomyelins, Staurosporine, Time Factors, Transfection, beta-Cyclodextrins

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          Interleukin-6 (IL-6) activates cells by binding to the membrane-bound IL-6 receptor (IL-6R) and subsequent formation of a glycoprotein 130 homodimer. Cells that express glycoprotein 130, but not the IL-6R, can be activated by IL-6 and the soluble IL-6R which is generated by shedding from the cell surface or by alternative splicing. Here we show that cholesterol depletion of cells with methyl-beta-cyclodextrin increases IL-6R shedding independent of protein kinase C activation and thus differs from phorbol ester-induced shedding. Contrary to cholesterol depletion, cholesterol enrichment did not increase IL-6R shedding. Shedding of the IL-6R because of cholesterol depletion is highly dependent on the metalloproteinase ADAM17 (tumor necrosis factor-alpha-converting enzyme), and the related ADAM10, which is identified here for the first time as an enzyme involved in constitutive and induced shedding of the human IL-6R. When combined with protein kinase C inhibition by staurosporine or rottlerin, breakdown of plasma membrane sphingomyelin or enrichment of the plasma membrane with ceramide also increased IL-6R shedding. The effect of cholesterol depletion was confirmed in human THP-1 and Hep3B cells and in primary human peripheral blood monocytes, which naturally express the IL-6R. For decades, high cholesterol levels have been considered harmful. This study indicates that low cholesterol levels may play a role in shedding of the membrane-bound IL-6R and thereby in the immunopathogenesis of human diseases.

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