Integrating signals from T-cell receptor and serum by T cells enhance translation of tumour necrosis factor-alpha

Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine prod uced by several cell types, including T cells upon antigen stimulation. Its production is crucial for the development of an early defence against many pathogens, but its beneficial effects are dependent on the strength and du ration of its expression. In this paper we present evidence indicating that serum increases translational efficiency of TNF-alpha in human peripheral blood mononuclear cells stimulated with superantigen. The increase in trans lation of TNF-alpha due to serum could be inhibited by the phosphatidylinos itol (PI) 3-K inhibitors, wortmannin and LY294002, suggesting that PI 3-K i s involved in the translational control of TNF-alpha by serum. Similarly to primary T cells, stimulation of Jurkat T cells with superantigen led to TN F-alpha secretion and this was up-regulated by serum. Transfection of Jurka t cells with a constitutively active form of PI 3-K alpha increased the pro duction of TNF-alpha in cells stimulated with superantigen. Additionally, w e used the specific inhibitors targeting ERK kinase and p38 mitogen-activat ed protein kinase (MAPK), potentially downstream of PI TNF-alpha mRNA was i nhibited by PD98059 or SB203580. These results suggest that, in T cells, ac tivation of PI 3-K is an important step in controlling TNF-alpha protein sy nthesis in response to growth factors.