Depletion of cellular cholesterol and lipid rafts increases shedding of CD30.
CD30, a lymphoid activation marker, is shed into the cell environment after endoproteolytic cleavage of its ectodomain. Soluble (s)CD30 is able to suppress the Th1-type immune response. Because high serum levels of sCD30 and cholesterol-lowering drugs seem to be beneficial in some Th1-type autoimmune diseases, we focused on a link between CD30 shedding and the amount of cellular cholesterol. Cholesterol depletion of human Hodgkin lymphoma- and non-Hodgkin lymphoma-derived cell lines by methyl-beta-cyclodextrin led to a down-regulation of membrane-bound CD30 and increased release of sCD30. Additionally, the cholesterol-interfering drugs lovastatin, cholesterol oxidase, and filipin increased CD30 shedding. Both the down-regulation of membrane-anchored CD30 and the release of sCD30 were dependent on metalloproteinases. Using specific inhibitors, we detected TNF-alpha converting enzyme (TACE) as the leading enzyme responsible for cholesterol-dependent CD30 shedding. A Triton X-100-based method for lipid raft isolation revealed that CD30 was partially present in lipid rafts, whereas TACE was localized in the nonraft fractions. Disintegration of lipid rafts by cholesterol depletion might therefore lead to dynamic interactions of CD30 with TACE, resulting in enhanced shedding of CD30. Our results suggest a possible role of cholesterol-dependent shedding of CD30 in the pathogenesis of immune diseases.
von Tresckow
Bastian
B
Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
Kallen
Karl-Josef
KJ
von Strandmann
Elke Pogge
EP
Borchmann
Peter
P
Lange
Hans
H
Engert
Andreas
A
Hansen
Hinrich P
HP
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism* / Q000502:physiology; D002789:Cholesterol Oxidase / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D003902:Detergents; D005372:Filipin / Q000494:pharmacology; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D021962:Membrane Microdomains / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors; D017830:Octoxynol; D012995:Solubility; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000494:pharmacology; D047392:beta-Cyclodextrins
D000924:Anticholesteremic Agents; D003505:Cyclodextrins; D003902:Detergents; D017730:Ki-1 Antigen; D019717:Tissue Inhibitor of Metalloproteinase-3; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D005372:Filipin; D017830:Octoxynol; D002784:Cholesterol; D008148:Lovastatin; D002789:Cholesterol Oxidase; D045726:Metalloproteases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human