Tumor Necrosis Factor-α, Sphingomyelinase, and Ceramide Inhibit Store-operated Calcium Entry in Thyroid FRTL-5 Cells

Törnquist, Kid; Malm, A M; Pasternack, Michael; Kronqvist, Robert; Björklund, Sonja; Tuominen, Raimo K.; Slotte, J. Peter

doi:10.1074/jbc.274.14.9370

Cited by 24 publications

(23 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like in mast cells, sphingosine that can be cleaved from ceramide by ceramidase was more potent than C2 ceramide. In contrast to mast cells, but similar to thyroid cells, C6 ceramide inhibited lymphocyte CRAC (30,31). Whereas nerve growth factor acutely inhibited CRAC in mast cells (30), CD95 in lymphocytes had to be stimulated for 1 h, possibly indicating a slower accumulation of sphingolipids.…”

Section: Discussionmentioning

confidence: 89%

“…In mast cells, the ceramide metabolite sphingosine inhibited CRAC more potently and faster than C2 ceramide, and nerve growth factor inhibited CRAC currents rapidly (30). In a thyroid cell line, tumor necrosis-factor ␣, bacterial sphingomyelinase, and C2 as well as C6 ceramide inhibited Ca 2ϩ influx (31).…”

Section: Discussionmentioning

confidence: 97%

“…CRAC is inhibited in mast cells via protein kinase C (28). Inhibition of Ca 2ϩ entry by sphingomyelinase products has been observed in T cells, mast cells, and thyroid cells (29)(30)(31). Mathes et al (30) analyzed in detail the effects of different sphingolipids on mast cells.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids

Lepple-Wienhues

Belka

Laun

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

169

View full text Add to dashboard Cite

Calcium influx through store-operated calcium release-activated calcium channels (CRAC) is required for T cell activation, cytokine synthesis, and proliferation. The CD95 (Apo-1͞Fas) receptor plays a role in self-tolerance and tumor immune escape, and it mediates apoptosis in activated T cells. In this paper we show that CD95-stimulation blocks CRAC and Ca 2؉ influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release. The block of Ca 2؉ entry is lacking in CD95-defective lpr lymphocytes as well as in ASM-defective cells and can be restored by retransfection of ASM. C2 ceramide, C6 ceramide, and sphingosine block CRAC reversibly, whereas the inactive dihydroceramide has no effect. CD95-stimulation or the addition of ceramide prevents store-operated Ca 2؉ The CD95-receptor induces apoptosis in lymphocytes and is critically involved in the maintenance of self-tolerance (reviewed in ref. 5). Expression of the CD95 ligand (CD95L) can create immune privileged sites (6, 7), and malignant tumors may escape from the immune attack by expressing high levels of CD95L (8,9).However, CD95 may have additional functions apart from lymphocyte apoptosis. First, freshly activated T lymphocytes express CD95 but are resistant to CD95-mediated apoptosis (10, 11). Second, in tumor patients, defective lymphocyte function rather than apoptotic deletion has been observed (12, 13). Third, mice inoculated with a CD95L-expressing tumor develop severe CD95-mediated defects in lymphocyte function (14). Fourth, the knockout of CD95-activated signaling molecules required for apoptosis does not, in contrast to CD95-knockout, result in lymphoproliferative disease (15,16). Thus, apoptosis may not represent the only function of CD95 in immune tolerance. Materials and MethodsCells. Jurkat T cells, Niemann-Pick Disease type A (NPDA), Daudi, and JY B cells were maintained in RPMI medium 1640, and LN18 and LN229 glioblastoma were maintained in DMEM (17). The stimulating monoclonal mouse anti-human CD95 (CH11; Upstate Biotechnology, Lake Placid, NY) was added at 100 ng͞ml. Apoptosis was assayed by nuclear fragmentation (Hoe33342, propidium iodide or SYTO 16; Molecular Probes) or FITC-annexin flow cytometry. Peripheral T lymphoblasts were prepared by using a Ficoll gradient, purified with nylon wool columns (Ͼ90% CD3 ϩ ), and stimulated with 1 g͞ml phythaemaglutinin (PHA) (24 h) plus 2.5 units͞ml IL-2 (4-6 days). Thymocytes were prepared from homozygous C57͞Bl6 lpr-and gld mice (ages 10-15 weeks). Transient transfection of NPDA cells was performed by electroporation with an expression vector encoding acidic sphingomyelinase (ASM) (pJK-asm, 15 g͞ml) and a Myc-tagged single chain (18). Twelve hours after electroporation viable cells were purified by Ficoll gradient centrifugation and cultured for an additional 24 h. After 36 h, Myc presented on the cell surface was stained with a monoclonal anti-Myc-antibody (9E10; American Type Culture Collection, Bethesda, MD) and a phycoerythrin-conjugated secondary antibody (18...

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids

Lepple-Wienhues

Belka

Laun

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

169

View full text Add to dashboard Cite

show abstract

“…Of note, inhibition of the CRACs has been described for other TNF superfamily members. For example, applying a model of Tg-evoked calcium entry, Törnquist et al (37) found that TNF-␣ inhibits store-operated calcium influx in a rat thyroid cell line. Moreover, Lepple-Wienhues et al (38) reported that CD95 stimulation inhibited activation of calcium channels and subsequent IL-2 synthesis in apoptosis-resistant Jurkat T cells.…”

Section: Discussionmentioning

confidence: 99%

Death Ligand TRAIL Induces No Apoptosis but Inhibits Activation of Human (Auto)antigen-Specific T Cells

Lünemann

Waiczies

Ehrlich

et al. 2002

The Journal of Immunology

127

View full text Add to dashboard Cite

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in susceptible cells, which can be both malignant and nontransformed. Despite homologies among the death ligands, there are great differences between the TRAIL system on the one hand and the TNF and CD95 systems on the other hand. In particular, TRAIL-induced apoptosis differs between rodents and man. Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector functions. Because we previously demonstrated that TRAIL does not induce apoptosis in human (auto)antigen-specific T cells, we now asked whether TRAIL exhibits other immunoregulatory properties in these cells. Active TRAIL inhibited calcium influx through store-operated calcium release-activated calcium channels, IFN-γ/IL-4 production, and proliferation. These effects were independent of APC, Ag specificity, and Th differentiation, and no differences were detected between healthy donors and multiple sclerosis patients. TRAIL affected neither the expression of the cell cycling inhibitor p27Kip1 nor the capacity of T cells to produce IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor does not induce T cell anergy. Instead, the TRAIL-induced hypoproliferation could be attributed to the down-regulation of the cyclin-dependent kinase 4, indicating a G1 arrest of the cell cycle. Thus, although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx.

show abstract

“…The lack of Ca 2+ influx during phagocytosis may explain the decreased phagocytic rate of aging (Whyte et al ., 1993;Butcher et al ., 2000) and fas-stimulated neutrophils (Ayub et al ., 2004 (Hueber, 2000). Activation of another member of the receptor superfamily to which fas belongs, tumour necrosis factor receptor (TNFR), also activates acid sphingomyelinase, and two TNFR ligands, TNF-α and NGF, also attenuate store-operated Ca 2+ entry in thyroid and mast cells, respectively (Mathes et al ., 1998;Tornquist et al ., 1999). However, ligation of fas may have other effects related to Ca 2+ signalling.…”

Section: + Influx In Immune Cellsmentioning

confidence: 99%

Signalling shutdown strategies in aging immune cells

Ayub

Hallett

2004

Aging Cell

View full text Add to dashboard Cite

SummaryIt is important for the resolution of inflammation that the number and activity of immune cells are reduced. Clearance of immune cells may be achieved by apoptosis and phagocytosis of cell fragments by macrophages. However, signalling shutdown by immune cells committed to apoptosis occurs early in the progression of these cells towards fragmentation and, it could be argued, is a key feature of apoptosis. There is surprisingly little known about the mechanisms that underlie this signalling shutdown, in particular the shutdown of Ca 2+ influx. The consequences and the potential mechanisms by which Ca 2+ influx shutdown is achieved are discussed. In addition, the potential consequences for cell signalling of cytochrome c release from mitochondria and of phosphatidylserine externalization are discussed. The aim of the review is therefore to highlight the evidence for various signalling shutdown strategies in immune cells that may limit their activity during progression towards apoptosis.

show abstract

Tumor Necrosis Factor-α, Sphingomyelinase, and Ceramide Inhibit Store-operated Calcium Entry in Thyroid FRTL-5 Cells

Cited by 24 publications

References 61 publications

Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids

Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids

Death Ligand TRAIL Induces No Apoptosis but Inhibits Activation of Human (Auto)antigen-Specific T Cells

Signalling shutdown strategies in aging immune cells

Contact Info

Product

Resources

About