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and IL-1
from Murine Macrophages1
School of Biological Sciences, University of Manchester, Manchester, United Kingdom
Interleukin-1 is a primary mediator of immune responses to injury and infection, but the mechanism of its cellular release is unknown. IL-1 exists as two agonist forms (IL-1
and IL-1
) present in the cytosol of activated monocytes/macrophages. IL-1 is synthesized as an inactive precursor that lacks a signal sequence, and its trafficking does not use the classical endoplasmic reticulum-Golgi route of secretion. Using primary cultured murine peritoneal macrophages, we demonstrate that P2X7 receptor activation causes release of IL-1 and IL-1 via a common pathway, dependent upon the release of Ca2+ from endoplasmic reticulum stores and caspase-1 activity. Increases in intracellular Ca2+ alone do not promote IL-1 secretion because a concomitant efflux of K+ through the plasmalemma is required. In addition, we demonstrate the existence of an alternative pathway for the secretion of IL-1, independent of P2X7 receptor activation, but dependent upon Ca2+ influx. The identification of these mechanisms provides insight into the mechanism of IL-1 secretion, and may lead to the identification of targets for the therapeutic modulation of IL-1 action in inflammation.
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