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Chronic exposure to TNF activates distinct TNF-R signaling pathways favouring cell survival in T lymphocytes

Tumour necrosis factor α (TNF) is a multipotent cytokine. Its role in the pathogenesis of rheumatoid arthritis (RA) is now well established. However, the signaling pathways activated by TNF in the context of chronic inflammation are less well understood. We have previously reported that chronic as opposed to acute TNF exposure induces non-deletional and reversible T cell hyporesponsiveness to T cell receptor ligation. To explore this further, we set out to explore more precisely how TNF signals in T lymphocytes, and in particular to determine whether chronic exposure to TNF activates a cascade of signaling pathways which are qualitatively or quantitatively distinct from those activated following short term stimulation. Initial experiments revealed that the p55 TNF-R is necessary and sufficient to induce T cell hyporesponsiveness. Accordingly, we focussed subsequent studies on p55 TNF-R signaling in a murine T cell hybridoma model. Over 8 days, repeated stimulation of T cells with pM doses of TNF leads to chronic, stable cytokine exposure throughout the culture period. At this low dose NF-κB is activated, while activation of other p55 TNF-R signaling pathways is much less pronounced. Within minutes of TNF-R ligation, high dose (nM) TNF induces strong activation of NF-κB and JNK in control T cells. In contrast, TNF-R ligation of T cells chronically exposed to low dose TNF leads to attenuation of JNK activation, while activation of NF-κB and ERK are spared. Preliminary data indicate that translocation of RelA to the nucleus is enhanced and sustained in TNF treated T cells. Together, the data indicate that the signaling pathways in T cells exposed to inflammatory cytokines for prolonged periods may be distinct from those activated by cytokines over much shorter periods. We speculate that in diseases such as RA, T cell effector responses may be promoted by selective activation of the ERK and NF-κB pathways, which promote T cell survival. The data also predict that the gene expression signature arising from chronic TNF stimulation should be distinct from the programme of gene transcription arising from short term TNF-R engagement.

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Cope, A., Vagenas, P., Panesar, M. et al. Chronic exposure to TNF activates distinct TNF-R signaling pathways favouring cell survival in T lymphocytes. Arthritis Res Ther 4 (Suppl 1), 47 (2002).

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