title: Role of acid sphingomyelinase bioactivity in human CD4+ T-cell activation and immune responses.
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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bai
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kokkotou
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Robson
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000639:Amitriptyline / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D018106:CD28 Antigens / Q000819:agonists / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D002331:Carnitine / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D061251:Primary Cell Culture; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D002518:Ceramides; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D000639:Amitriptyline; D013108:Sphingomyelin Phosphodiesterase; D007099:Imipramine; D002331:Carnitine