| Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized LDL and oxidized LDL immune complexes: role in phagocytosis and cytokine release. | |
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MedLine Citation:
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PMID: 22236141 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Oxidized low-density lipoprotein (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to formation of lipid-laden macrophages (foam cells). Fcγ receptors mediate uptake of oxLDL-IC, whereas scavenger receptors internalize oxLDL. We have previously reported that oxLDL-IC but not free oxLDL activate macrophages and prolong their survival. Sphingomyelin is a major constituent of cell membranes and lipoprotein particles and acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin to generate the bioactive lipid ceramide. ASMase exists in two forms: lysosomal (L-ASMase) and secretory (S-ASMase). In this study we examined whether oxLDL and oxLDL-IC regulate ASMase differently, and whether ASMase mediates monocyte/macrophage activation and cytokine release. oxLDL-IC but not oxLDL induced early and consistent release of catalytically active S-ASMase. oxLDL-IC also consistently stimulated L-ASMase activity, whereas oxLDL induced a rapid transient increase in L-ASMase activity before it steadily declined below baseline. Prolonged exposure to oxLDL increased L-ASMase activity; however, activity remained significantly lower than that induced by oxLDL-IC. Further studies were aimed at defining the function of the activated ASMase. In response to oxLDL-IC, heat shock protein 70B' (HSP70B') was up-regulated and localized with redistributed ASMase in the endosomal compartment outside the lysosome. Treatment with oxLDL-IC induced the formation and release of HSP70- and IL-1β-containing exosomes via an ASMase-dependent mechanism. Taken together, the results suggest that oxLDL and oxLDL-IC differentially regulate ASMase activity, and the pro-inflammatory responses to oxLDL-IC are mediated by prolonged activation of ASMase. These findings may contribute to increased understanding of mechanisms mediating macrophage involvement in atherosclerosis. |
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Authors:
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Jean-Philip Truman; Mohammed M Al Gadban; Kent J Smith; Russell W Jenkins; Nalini Mayroo; Gabriel Virella; Maria F Lopes-Virella; Alicja Bielawska; Yusuf A Hannun; Samar M Hammad |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-12 |
Journal Detail:
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Title: Immunology Volume: - ISSN: 1365-2567 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0374672 Medline TA: Immunology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Journal compilation © 2012 Blackwell Publishing Ltd. |
Affiliation:
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Department of Regenerative Medicine & Cell Biology Department of Biochemistry & Molecular Biology Department of Microbiology and Immunology Division of Endocrinology, Medical University of South Carolina, Charleston, SC 29425 Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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