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Kinetics and Mechanism of ATP-Dependent IL-1ß Release from Microglial Cells¹

Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Center of Biotechnology, University of Ferrara, Ferrara, Italy

Endotoxin-dependent release of IL-1ß from mouse microglial cells is a very inefficient process, as it is slow and leads to accumulation of a modest amount of extracellular cytokine. Furthermore, secreted IL-1ß is mostly in the procytokine unprocessed form. Addition of extracellular ATP to LPS-primed microglia caused a burst of release of a large amount of processed IL-1ß. ATP had no effect on the accumulation of intracellular pro-IL-1ß in the absence of LPS. In LPS-treated cells, ATP slightly increased the synthesis of pro-IL-1ß. Optimal ATP concentration for IL-1ß secretion was between 3 and 5 mM, but significant release could be observed at concentrations as low as 1 mM. At all ATP concentrations IL-1ß release could be inhibited by increasing the extracellular K⁺ concentration. ATP-dependent IL-1ß release was also inhibited by 90 and 60% by the caspase inhibitors YVAD and DEVD, respectively. Accordingly, in ATP-stimulated microglia, the p20 proteolytic fragment derived from activation of the IL-1-ß-converting enzyme could be detected by immunoblot analysis. These experiments show that in mouse microglial cells extracellular ATP triggers fast maturation and release of intracellularly accumulated IL-ß by activating the IL-1-ß-converting enzyme/caspase 1.