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Am J Physiol Cell Physiol (March 26, 2003). doi:10.1152/ajpcell.00070.2003
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Submitted on February 21, 2003
Accepted on March 20, 2003

Essential role for Ca2+ in the regulation of IL-1{beta}secretion by the P2X7 nucleotide receptor in monocytes, macrophages, and HEK293 fibroblasts

Lalitha Gudipaty1, Jonathan Munetz1, Philip A. Verhoef1, and George R. Dubyak1*

1 Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA

* To whom correspondence should be addressed. E-mail: gxd3{at}po.cwru.edu.

Interleukin-1{beta} (IL-1{beta}) 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 classical secretory pathways. Efficient externalization of IL-1{beta} 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 non-selective cation channels facilitates secretion of IL-1{beta} remain unclear. Here, we demonstrate a pivotal role for a sustained increase in cytosolic Ca2+ to potentiate secretion of IL-1{beta} via the P2X7 receptors. Using HEK 293 fibroblasts engineered to co-express P2X7 receptors with mature IL-1{beta}, we show that activation of P2X7 receptors results in a rapid secretion of mIL-1{beta} by a process(s) that is dependent on influx of extracellular Ca2+ and a sustained rise in cytosolic Ca2+. Moreover, reduction in extracellular Ca 2+ attenuates ~ 90 % of P2X7 receptor-mediated IL-1{beta} secretion but has no effect on enzymatic processing of proIL-1{beta} to mIL-1{beta} by caspase-1. Similar experiments with THP-1 human monocytes and Bac1.2F5 murine macrophages confirm the unique role of Ca 2+ in P2X7 receptor-mediated secretion of IL-1{beta}. 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{beta} and that this can be repressed by inhibitors of P2X7 receptors. Taken together, we clarify an essential role for Ca 2+ in ATP-induced IL-1{beta} secretion and indicate an additional role of P2X7 receptors as enhancers of the secretory apparatus by which IL-1{beta} is released.




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