{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:13:48Z","timestamp":1791231228172,"version":"4.1.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2005,4,7]],"date-time":"2005-04-07T00:00:00Z","timestamp":1112832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Birmingham Arthritis Appeals Trust"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tumor necrosis factor \u03b1 (TNF-\u03b1) is a potent, pleiotrophic cytokine, which is proinflammatory but can also suppress T lymphocyte function. In chronic inflammatory disease such as rheumatoid arthritis, exposure of T cells to TNF-\u03b1 alters their ability to mount a response by modulating the T cell receptor (TCR) signaling pathway, but the mechanisms involved remain obscure. Here, we investigated the specific role of TNF receptor 1 (TNFR1) signaling in the modulation of the TCR signaling pathway. We observed a down-regulation of the intracellular calcium ([Ca2+]i) signal in Jurkat T cells after just 30 min exposure to TNF-\u03b1, and maximum suppression was reached after 3 h. This effect was transient, and signals returned to normal after 12 h. This depression of [Ca2+]i was also observed in human CD4+ T lymphocytes. The change in Ca2+ signal was related to a decrease in the plasma membrane Ca2+ influx, which was apparent even when the TCR signal was bypassed using thapsigargin to induce a Ca2+ influx. The role of TNF-\u03b1-induced activation of the sphingolipid cascade in this pathway was examined. The engagement of TNFR1 by TNF-\u03b1 led to a time-dependent increase in acid sphingomyelinase (SMase; ASM) activity, corresponding with a decrease in cellular sphingomyelin. In parallel, there was an increase in cellular ceramide, which correlated directly with the decrease in the magnitude of the Ca2+ response to phytohemagglutinin. Exogenous addition of SMase or ceramide mimicked the effects of TNFR1 signals on Ca2+ responses in Jurkat T cells. Direct evidence for the activation of ASM in this pathway was provided by complete abrogation of the TNF-\u03b1-induced inhibition of the Ca2+ influx in an ASM-deficient murine T cell line (OT-II+\/+ASM\u2212\/\u2212). This potent ability of TNF-\u03b1 to rapidly modulate the TCR Ca2+ signal via TNFR1-induced ASM activation can explain its suppressive effect on T cell function. This TNFR1 signaling pathway may play a role as an important regulator of T cell responses.<\/jats:p>","DOI":"10.1189\/jlb.1003456","type":"journal-article","created":{"date-parts":[[2005,4,7]],"date-time":"2005-04-07T20:33:52Z","timestamp":1112906032000},"page":"266-278","source":"Crossref","is-referenced-by-count":45,"title":["TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-operated Ca2+ influx"],"prefix":"10.1093","volume":"78","author":[{"given":"Leigh D","family":"Church","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Division of Immunity and Infection, University of Birmingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Hessler","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E","family":"Goodall","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Division of Immunity and Infection, University of Birmingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Rider","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Division of Immunity and Infection, University of Birmingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Creg J","family":"Workman","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children's Research Hospital , Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario A A","family":"Vignali","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children's Research Hospital , Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A","family":"Bacon","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Division of Immunity and Infection, University of Birmingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erich","family":"Gulbins","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Division of Immunity and Infection, University of Birmingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2005,4,7]]},"reference":[{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.4049\/jimmunol.138.6.1786","article-title":"Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-\u03b1: induction of TNF receptors on human T cells and TNF-\u03b1-mediated enhancement of T cell responses","volume":"138","author":"Scheurich","year":"1987","journal-title":"J. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/0167-5699(88)91353-9","article-title":"The role of cachectin\/TNF in endotoxic shock and cachexia","volume":"9","author":"Cerami","year":"1988","journal-title":"Immunol. Today"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.4049\/jimmunol.140.8.2639","article-title":"Comparative effects of tumor necrosis factor-\u03b1 and IL-1 \u03b2 on mitogen-induced T cell activation","volume":"140","author":"Hackett","year":"1988","journal-title":"J. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"531","DOI":"10.4049\/jimmunol.140.2.531","article-title":"Enhancement of antigen- and mitogen-induced human T lymphocyte proliferation by tumor necrosis factor-\u03b1","volume":"140","author":"Yokota","year":"1988","journal-title":"J. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/oxfordjournals.bmb.a072967","article-title":"Cytokine expression in chronic inflammatory disease","volume":"51","author":"Brennan","year":"1995","journal-title":"Br. Med. Bull."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1172\/JCI117394","article-title":"Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor\/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis","volume":"94","author":"Cope","year":"1994","journal-title":"J. Clin. Invest."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1084\/jem.185.9.1573","article-title":"Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling","volume":"185","author":"Cope","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"5495","DOI":"10.4049\/jimmunol.166.9.5495","article-title":"Prolonged exposure of T cells to TNF down-regulates TCR \u0396 and expression of the TCR\/CD3 complex at the cell surface","volume":"166","author":"Isomaki","year":"2001","journal-title":"J. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0952-7915(98)80087-3","article-title":"Regulation of autoimmunity by proinflammatory cytokines","volume":"10","author":"Cope","year":"1998","journal-title":"Curr. Opin. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.4049\/jimmunol.154.6.2904","article-title":"Both TNF receptors are required for TNF-mediated induction of apoptosis in PC60 cells","volume":"154","author":"Vandenabeele","year":"1995","journal-title":"J. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.4049\/jimmunol.153.5.1963","article-title":"TNF receptors TR60 and TR80 can mediate apoptosis via induction of distinct signal pathways","volume":"153","author":"Grell","year":"1994","journal-title":"J. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S0898-6568(01)00262-5","article-title":"TNF receptor subtype signaling: differences and cellular consequences","volume":"14","author":"MacEwan","year":"2002","journal-title":"Cell. Signal."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/S0092-8674(00)80169-5","article-title":"FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase","volume":"86","author":"Adam-Klages","year":"1996","journal-title":"Cell"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/jlb.63.6.678","article-title":"Distinct adapter proteins mediate acid versus neutral sphingomyelinase activation through the p55 receptor for tumor necrosis factor","volume":"63","author":"Adam-Klages","year":"1998","journal-title":"J. Leukoc. Biol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"13795","DOI":"10.1073\/pnas.96.24.13795","article-title":"Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids","volume":"96","author":"Lepple-Wienhues","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S1388-1981(00)00042-1","article-title":"Physiology and pathophysiology of sphingolipid metabolism and signaling","volume":"1485","author":"Huwiler","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0167-5699(00)01725-4","article-title":"Sphingolipids: second messengers, mediators and raft constituents in signaling","volume":"21","author":"Prieschl","year":"2000","journal-title":"Immunol. Today"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/386855a0","article-title":"Differential activation of transcription factors induced by Ca2+ response amplitude and duration","volume":"386","author":"Dolmetsch","year":"1997","journal-title":"Nature"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signaling","volume":"1","author":"Berridge","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"6007","DOI":"10.1073\/pnas.92.13.6007","article-title":"The inositol 1,4,5-trisphosphate receptor is essential for T-cell receptor signaling","volume":"92","author":"Jayaraman","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"12135","DOI":"10.1016\/S0021-9258(18)98869-1","article-title":"T-cell antigen receptor ligation induces tyrosine phosphorylation of phospholipase C-\u03b3 1","volume":"266","author":"Secrist","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1084\/jem.175.1.285","article-title":"Phospholipase C-\u03b3 1 association with CD3 structure in T cells","volume":"175","author":"Dasgupta","year":"1992","journal-title":"J. Exp. Med."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/361315a0","article-title":"Inositol trisphosphate and calcium signaling","volume":"361","author":"Berridge","year":"1993","journal-title":"Nature"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1074\/jbc.270.6.2833","article-title":"The human type 1 inositol 1,4,5-trisphosphate receptor from T lymphocytes. Structure, localization, and tyrosine phosphorylation","volume":"270","author":"Harnick","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0143-4160(86)90026-6","article-title":"A model for receptor-regulated calcium entry","volume":"7","author":"Putney","year":"1986","journal-title":"Cell Calcium"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/86318","article-title":"Gene regulation mediated by calcium signals in T lymphocytes","volume":"2","author":"Feske","year":"2001","journal-title":"Nat. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1073\/pnas.91.7.2873","article-title":"Intracellular calcium dependence of gene expression in single T lymphocytes","volume":"91","author":"Negulescu","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1046\/j.1440-1711.1998.00709.x","article-title":"Defective TCR expression in transgenic mice constructed using cDNA-based \u03b1- and \u03b2-chain genes under the control of heterologous regulatory elements","volume":"76","author":"Barnden","year":"1998","journal-title":"Immunol. Cell Biol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/ng0795-288","article-title":"Acid sphingomyelinase-deficient mice: a model of types A and B Niemann-Pick disease","volume":"10","author":"Horinouchi","year":"1995","journal-title":"Nat. Genet."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1016\/S0021-9258(19)83641-4","article-title":"A new generation of Ca2+ indicators with greatly improved fluorescence properties","volume":"260","author":"Grynkiewicz","year":"1985","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1042\/bj3130909","article-title":"Submicromolar La3+ concentrations block the calcium release-activated channel, and impair CD69 and CD25 expression in CD3- or thapsigargin-activated Jurkat cells","volume":"313","author":"Aussel","year":"1996","journal-title":"Biochem. J."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/1074-7613(95)90142-6","article-title":"FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway","volume":"2","author":"Gulbins","year":"1995","journal-title":"Immunity"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0092-8674(00)80448-1","article-title":"Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells","volume":"91","author":"Grassme","year":"1997","journal-title":"Cell"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1006\/abio.1999.4157","article-title":"Enzymatic measurement of sphingosine 1-phosphate","volume":"272","author":"Edsall","year":"1999","journal-title":"Anal. Biochem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1073\/pnas.81.13.4169","article-title":"Role of T3 surface molecules in human T-cell activation: T3-dependent activation results in an increase in cytoplasmic free calcium","volume":"81","author":"Weiss","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/BF01986687","article-title":"Thapsigargin, a novel molecular probe for studying intracellular calcium release and storage. 1989","volume":"43","author":"Thastrup","year":"1994","journal-title":"Agents Actions"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"5054","DOI":"10.1016\/S0021-9258(17)37653-6","article-title":"Regulation by sphingomyelinase and sphingosine of Ca2+ signals elicited by CD3 monoclonal antibody, thapsigargin, or ionomycin in the Jurkat T cell line","volume":"269","author":"Breittmayer","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1096\/fj.02-1038com","article-title":"The sphingosine kinase 1\/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-\u03b1","volume":"17","author":"Pettus","year":"2003","journal-title":"FASEB J."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"9292","DOI":"10.1073\/pnas.88.20.9292","article-title":"The two different receptors for tumor necrosis factor mediate distinct cellular responses","volume":"88","author":"Tartaglia","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/art.1780310816","article-title":"Detection of tumor necrosis factor \u03b1 but not tumor necrosis factor \u03b2 in rheumatoid arthritis synovial fluid and serum","volume":"31","author":"Saxne","year":"1988","journal-title":"Arthritis Rheum."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1046\/j.0019-2805.2001.01321.x","article-title":"Calcium channels in lymphocytes","volume":"104","author":"Grafton","year":"2001","journal-title":"Immunology"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"33995","DOI":"10.1074\/jbc.274.48.33995","article-title":"[Ca(2+)](i) oscillation frequency regulates agonist-stimulated NF-\u03baB transcriptional activity","volume":"274","author":"Hu","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S1074-7613(00)80285-X","article-title":"Different nuclear signals are activated by the B cell receptor during positive versus negative signaling","volume":"6","author":"Healy","year":"1997","journal-title":"Immunity"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/31960","article-title":"Calcium oscillations increase the efficiency and specificity of gene expression","volume":"392","author":"Dolmetsch","year":"1998","journal-title":"Nature"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"25020","DOI":"10.1074\/jbc.273.39.25020","article-title":"Calcium release-activated calcium current (ICRAC) is a direct target for sphingosine","volume":"273","author":"Mathes","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"11934","DOI":"10.1074\/jbc.275.16.11934","article-title":"Assembly of Trp1 in a signaling complex associated with caveolin-scaffolding lipid raft domains","volume":"275","author":"Lockwich","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"8409","DOI":"10.1074\/jbc.M009948200","article-title":"Isoform-specific localization of voltage-gated K+ channels to distinct lipid raft populations\u2014targeting of Kv1.5 to 3 caveolae","volume":"276","author":"Martens","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"7070","DOI":"10.1038\/sj.onc.1207146","article-title":"Raft ceramide in molecular medicine","volume":"22","author":"Gulbins","year":"2003","journal-title":"Oncogene"},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/eji.1830250612","article-title":"Altered T lymphocyte signaling in rheumatoid arthritis","volume":"25","author":"Allen","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1002\/1529-0131(200006)43:6<1257::AID-ANR8>3.0.CO;2-Q","article-title":"Dysregulated intracellular Ca2 stores and Ca2 signaling in synovial fluid T lymphocytes from patients with chronic inflammatory arthritis","volume":"43","author":"Carruthers","year":"2000","journal-title":"Arthritis Rheum."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1046\/j.1365-2249.1996.d01-768.x","article-title":"Characterization of altered calcium signaling in T lymphocytes from patients with rheumatoid arthritis (RA)","volume":"105","author":"Carruthers","year":"1996","journal-title":"Clin. Exp. Immunol."},{"key":"2023033022500372100_","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.febslet.2005.01.051","article-title":"Persistent TNF-\u03b1 exposure impairs store operated calcium influx in CD4+ T lymphocytes","volume":"579","author":"Church","year":"2005","journal-title":"FEBs. Letters"}],"container-title":["Journal of Leukocyte Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/78\/1\/266\/49648366\/jlb0266.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/78\/1\/266\/49648366\/jlb0266.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T17:18:43Z","timestamp":1683047923000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jleukbio\/article\/78\/1\/266\/6922638"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,4,7]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2005,4,7]]},"published-print":{"date-parts":[[2005,4,7]]}},"URL":"https:\/\/doi.org\/10.1189\/jlb.1003456","relation":{},"ISSN":["0741-5400","1938-3673"],"issn-type":[{"value":"0741-5400","type":"print"},{"value":"1938-3673","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2005,7]]},"published":{"date-parts":[[2005,4,7]]}}}