In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 78, No. 1 ( 2005-04-07), p. 266-278
Abstract:
Tumor necrosis factor α (TNF-α) 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-α 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-α, 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-α-induced activation of the sphingolipid cascade in this pathway was examined. The engagement of TNFR1 by TNF-α 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-α-induced inhibition of the Ca2+ influx in an ASM-deficient murine T cell line (OT-II+/+ASM−/−). This potent ability of TNF-α 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.
Type of Medium:
Online Resource
ISSN:
0741-5400
,
1938-3673
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2005
detail.hit.zdb_id:
2026833-6
SSG:
12
