Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages.
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.
Brough
David
D
School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
Le Feuvre
Rosalind A
RA
Wheeler
Rachel D
RD
Solovyova
Natasha
N
Hilfiker
Sabine
S
Rothwell
Nancy J
NJ
Verkhratsky
Alex
A
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000276:immunology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D007375:Interleukin-1 / Q000378:metabolism*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011188:Potassium / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058486:Receptors, Purinergic P2X7
D007375:Interleukin-1; D008070:Lipopolysaccharides; C546469:P2rx7 protein, mouse; D020033:Protein Isoforms; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D011188:Potassium; D002118:Calcium