Abstract
Effector T cells and T cells from patients with systemic lupus erythematosus (SLE) express increased levels of the spleen tyrosine kinase (Syk). Syk binds to the T cell receptor (TCR)-CD3 complex and transduces the TCR-mediated signal in the cell more efficiently than the canonical CD3ζ chain. The reasons for the increased expression of Syk are unclear. In the present study, we found that Syk is regulated by the transcription factor c-Jun in cooperation with Ets2. c-Jun and Ets2 bound to the SYK promoter in close proximity and increased the promoter activity in a specific manner. Disruption of c-Jun and Ets2 expression by siRNA resulted in decreased expression of Syk. Overexpression of c-Jun but not Ets2 resulted in increase in Syk protein. c-Jun and Ets2 co-immunoprecipitated and had an additive effect on Syk expression. c-Jun-driven SYK promoter activation showed a similar pattern in B cells; however, as expected, basal promoter activity was much higher in B cells as compared with T cells. Overexpression of c-Jun led to increase in intracytoplasmic calcium flux following TCR stimulation. Moreover, we found that SLE T cells had increased levels of c-Jun at baseline and phosphorylated c-Jun upon activation. Finally, disruption of c-Jun and Ets2 in SLE T cells resulted in a decrease in calcium flux upon TCR stimulation. In conclusion, c-Jun in cooperation with Ets2 increases the expression of Syk and contributes to Syk-mediated heightened calcium responses in SLE T cells.
Highlights
spleen tyrosine kinase (Syk) is increased in effector T cells and systemic lupus erythematosus (SLE) T cells and contributes to increased T cell receptor (TCR) activation-induced intracytoplasmic calcium flux
We found that Syk is regulated by the transcription factor c-Jun in cooperation with Ets2. c-Jun and Ets2 bound to the SYK promoter in close proximity and increased the promoter activity in a specific manner
Overexpression of c-Jun but not Ets2 resulted in increase in Syk protein. c-Jun and Ets2 co-immunoprecipitated and had an additive effect on Syk expression. c-Jun-driven SYK promoter activation showed a similar pattern in B cells; as expected, basal promoter activity was much higher in B cells as compared with T cells
Summary
Syk is increased in effector T cells and SLE T cells and contributes to increased TCR activation-induced intracytoplasmic calcium flux. Results: c-Jun in cooperation with Ets increases the transcription of SYK and the intracytoplasmic calcium flux. Effector T cells and T cells from patients with systemic lupus erythematosus (SLE) express increased levels of the spleen tyrosine kinase (Syk). The spleen tyrosine kinase (Syk) is increased in total amount and level of phosphorylation in systemic lupus erythematosus (SLE) T cells and associates with the T cell receptor (TCR)-CD3 complex, serving as a main signal transducer [1]. This event contributes to the hyperexcitable phenotype of SLE T cells, i.e. the robust intracytoplasmic flux of calcium following the. The two transcription factors cooperate to increase the expression of Syk, contributing to higher calcium influx in T cells
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