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Comparative Study
. 2003 Mar 15;170(6):3029-36.
doi: 10.4049/jimmunol.170.6.3029.

Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages

David Brough  1 , Rosalind A Le Feuvre, Rachel D Wheeler, Natasha Solovyova, Sabine Hilfiker, Nancy J Rothwell, Alex Verkhratsky
Affiliations
Comparative Study

Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages

David Brough et al. J Immunol. .

Abstract

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 alpha and IL-1 beta) present in the cytosol of activated monocytes/macrophages. IL-1 beta 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 beta and IL-1 alpha via a common pathway, dependent upon the release of Ca(2+) from endoplasmic reticulum stores and caspase-1 activity. Increases in intracellular Ca(2+) 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 alpha, independent of P2X7 receptor activation, but dependent upon Ca(2+) 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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