Shedding Cytokines

Interleukin-1β (IL-1β) is a cytokine released from monocytes, the release of which requires two signals: a priming signal that stimulates the synthesis of IL-1β precursor and a second signal that triggers release and activation of the precursor through cleavage to an active form. Adenosine triphosphate (ATP) acting through purinergic P2X 7 receptors is one of two known physiological signals that trigger release of active IL-1β. IL-1β is unusual for a secreted protein in that it lacks a secretory signal and is not released by classic calcium-stimulated secretion through fusion of vesicles formed during synthesis through the secretory pathway (endoplasmic reticulum to Golgi to regulated secretory vesicle). MacKenzie et al. show that human embryonic kidney (HEK) cells transfected to express the P2X 7 receptors or monocytes, which endogenously express P2X 7 receptors, undergo rapid microvesicle shedding and reversible exposure of the inner leaflet lipid phosphatidylserine upon exposure to ATP. In monocytes primed with lipopolysaccharide to stimulate IL-1β production, treatment with ATP led to release of precursor and cleaved active IL-1β in microvesicles shed from the membranes of the cells in a process that required extracellular calcium. Microvesicles were visualized by microscopy, and membrane loss was detected by a decrease in membrane capacitance. Medium containing the IL-1β microvesicles was capable of activating IL-1 receptors in two separate assays, suggesting that the microvesicles are a physiological delivery system for this cytokine. A. MacKenzie, H. L. Wilson, E. Kiss-Toth, S. K. Dower, R. A. North, A. Surprenant, Rapid secretion of interleukin-1β by microvesicle shedding. Immunity 8 , 825-835 (2001). [Online Journal]