Abstract
Acid sphingomyelinase (ASM), a lipid hydrolase enzyme, has the potential to modulate various cellular activation responses via the generation of ceramide and by interaction with cellular receptors. We have hypothesized that ASM modulates CD4(+) T-cell receptor activation and impacts immune responses. We first observed interactions of ASM with the intracellular domains of both CD3 and CD28. ASM further mediates T-cell proliferation after anti-CD3/CD28 antibody stimulation and alters CD4(+) T-cell activation signals by generating ceramide. We noted that various pharmacological inhibitors of ASM or knockdown of ASM using small hairpin RNA inhibit CD3/CD28-mediated CD4(+) T-cell proliferation and activation. Furthermore, such blockade of ASM bioactivity by biochemical inhibitors and/or molecular-targeted knockdown of ASM broadly abrogate T-helper cell responses. In conclusion, we detail immune, pivotal roles of ASM in adaptive immune T-cell responses, and propose that these pathways might provide novel targets for the therapy of autoimmune and inflammatory diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity / genetics*
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Amitriptyline / pharmacology
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Antibodies / pharmacology
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CD28 Antigens / agonists
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CD28 Antigens / genetics
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CD28 Antigens / immunology
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CD3 Complex / genetics
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CD3 Complex / immunology
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Carnitine / pharmacology
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Cell Proliferation / drug effects
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Ceramides / biosynthesis
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Ceramides / immunology
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation
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Humans
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Imipramine / pharmacology
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Lymphocyte Activation / drug effects*
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Primary Cell Culture
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Protein Binding
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Protein Structure, Tertiary
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Signal Transduction
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Sphingomyelin Phosphodiesterase / antagonists & inhibitors
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Sphingomyelin Phosphodiesterase / genetics
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Sphingomyelin Phosphodiesterase / immunology*
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / drug effects
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T-Lymphocytes, Helper-Inducer / immunology*
Substances
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Antibodies
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CD28 Antigens
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CD3 Complex
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Ceramides
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Enzyme Inhibitors
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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Amitriptyline
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Sphingomyelin Phosphodiesterase
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Imipramine
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Carnitine