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© The Rockefeller University Press, 0021-9525/1997//1635 $5.00
The Journal of Cell Biology, Volume 139, Number 7, , 1997 1635-1643

Article

Extracellular ATP Activates Transcription Factor NF-{kappa}B through the P2Z Purinoreceptor by Selectively Targeting NF-{kappa}B p65 (RelA)



Davide Ferrari, Sebastian Wesselborg, Manuel K.A. Bauer, and Klaus Schulze-Osthoff

Department of Internal Medicine I, Medical Clinics, Eberhard-Karls-University, D-72076 Tübingen, Germany

Cells of the macrophage lineage express a peculiar surface receptor for extracellular ATP, designated P2Z/P2X7 purinergic receptor, that induces pore formation and collapse of the plasma membrane potential. Although the function of the P2Z receptor is largely unknown, accumulating evidence implicates its role in cell signaling and immune reactions. Here, we investigated the effect of P2Z receptor ligation on the activation of NF-{kappa}B, a transcription factor controlling cytokine expression and apoptosis. Exposure of microglial cells to ATP but not other nucleotides resulted in potent NF-{kappa}B activation. This effect was specifically mediated by the P2Z receptor, because selective receptor antagonists prevented NF-{kappa}B activation. NF-{kappa}B activation required reactive oxygen intermediates and proteases of the caspase family, because it was abolished by antioxidants and specific protease inhibitors. The subunit composition of the ATP-induced NF- {kappa}B–DNA complex was rather unusual. Whereas exposure to LPS-induced prototypical NF-{kappa}B p50 homo- and p65 (RelA)/p50 heterodimers, ATP stimulation resulted in the sole appearance of a p65 homodimer. This is the first demonstration that a certain stimulus activates a particular NF-{kappa}B subunit. Because different NF-{kappa}B complexes exhibit distinct transcriptional and DNA-binding activities, ATP may control the expression of a subset of NF-{kappa}B target genes distinct from those activated by classical proinflammatory mediators.

Abbreviations used in this paper: EMSA, electrophoretic mobility shift assay; ICE, IL-1β-converting enzyme; IL, interleukin; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; PDTC, pyrrolidine dithiocarbamate; RA, receptor antagonist; ROI, reactive oxygen intermediate; TNF, tumor necrosis factor.

D.F. acknowledges a fellowship from FEBS and the Vigoni (DAAD/ CRUI) programme. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 364/A7, Schu 1180/1-1).

Address all correspondence to Klaus Schulze-Osthoff, Medical Clinics, Department of Internal Medicine I, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. Tel.: 49 7071 29 84113. Fax: 49 7071 29 5865.


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