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RECEPTORS AND SIGNAL TRANSDUCTION

Essential role for Ca²⁺ in regulation of IL-1 secretion by P2X₇ nucleotide receptor in monocytes, macrophages, and HEK-293 cells

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106

Submitted 21 February 2003 ; accepted in final form 20 March 2003

Interleukin (IL)-1 is a proinflammatory cytokine that elicits the majority of its biological activity extracellularly, but the lack of a secretory signal sequence prevents its export via classic secretory pathways. Efficient externalization of IL-1 in macrophages and monocytes can occur via stimulation of P2X₇ nucleotide receptors with extracellular ATP. However, the exact mechanisms by which the activation of these nonselective cation channels facilitates secretion of IL-1 remain unclear. Here we demonstrate a pivotal role for a sustained increase in cytosolic Ca²⁺ to potentiate secretion of IL-1 via the P2X₇ receptors. Using HEK-293 cells engineered to coexpress P2X₇ receptors with mature IL-1 (mIL-1), we show that activation of P2X₇ receptors results in a rapid secretion of mIL-1 by a process(es) that is dependent on influx of extracellular Ca²⁺ and a sustained rise in cytosolic Ca²⁺. Moreover, reduction in extracellular Ca²⁺ attenuates 90% of P2X₇ receptor-mediated IL-1 secretion but has no effect on enzymatic processing of precursor IL-1 (proIL-1) to mIL-1 by caspase-1. Similar experiments with THP-1 human monocytes and Bac1.2F5 murine macrophages confirm the unique role of Ca²⁺ in P2X₇ receptor-mediated secretion of IL-1. In addition, we report that cell surface expression of P2X₇ receptors in the absence of external stimulation also results in enhanced release of IL-1 and that this can be repressed by inhibitors of P2X₇ receptors. We clarify an essential role for Ca²⁺ in ATP-induced IL-1 secretion and indicate an additional role of P2X₇ receptors as enhancers of the secretory apparatus by which IL-1 is released.

interleukin-1; calcium ion; adenosine 5'-triphosphate; P2X₇ receptors

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