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J. Biol. Chem., Vol. 278, Issue 3, 1549-1560, January 17, 2003

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Signaling through P2X7 Receptor in Human T Cells Involves p56^lck, MAP Kinases, and Transcription Factors AP-1 and NF-B^*

Vadim Budagian^§, Elena Bulanova^§¶, Luba Brovko, Zane Orinska, Raja Fayad^**, Ralf Paus, and Silvia Bulfone-Paus

From the  Department of Immunology and Cellular Biology, Research Center Borstel, D-23845 Borstel, Germany, the  Department of Food Science, University of Guelph, Guelph, Ontario N1G 2W1, Canada, the ^** Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, and the  Department of Dermatology, University Hospital Eppendorf, University of Hamburg, D-20246 Hamburg, Germany

ATP-gated ion channel P2X receptors are expressed on the surface of most immune cells and can trigger multiple cellular responses, such as membrane permeabilization, cytokine production, and cell proliferation or apoptosis. Despite broad distribution and pleiotropic activities, signaling pathways downstream of these ionotropic receptors are still poorly understood. Here, we describe intracellular signaling events in Jurkat cells treated with millimolar concentrations of extracellular ATP. Within minutes, ATP treatment resulted in the phosphorylation and activation of p56^lck kinase, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase but not p38 kinase. These effects were wholly dependent upon the presence of extracellular Ca²⁺ ions in the culture medium. Nevertheless, calmodulin antagonist calmidazolium and CaM kinase inhibitor KN-93 both had no effect on the activation of p56^lck and ERK, whereas a pretreatment of Jurkat cells with MAP kinase kinase inhibitor P098059 was able to abrogate phosphorylation of ERK. Further, expression of c-Jun and c-Fos proteins and activator protein (AP-1) DNA binding activity were enhanced in a time-dependent manner. In contrast, DNA binding activity of NF-B was reduced. ATP failed to stimulate the phosphorylation of ERK and c-Jun N-terminal kinase and activation of AP-1 in the p56^lck-deficient isogenic T cell line JCaM1, suggesting a critical role for p56^lck kinase in downstream signaling. Regarding the biological significance of the ATP-induced signaling events we show that although extracellular ATP was able to stimulate proliferation of both Jurkat and JCaM1 cells, an increase in interleukin-2 transcription was observed only in Jurkat cells. The nucleotide selectivity and pharmacological profile data supported the evidence that the ATP-induced effects in Jurkat cells were mediated through the P2X7 receptor. Taken together, these results demonstrate the ability of extracellular ATP to activate multiple downstream signaling events in a human T-lymphoblastoid cell line.

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