Pannexin-1-dependent caspase-1 activation and secretion of IL-1beta is regulated by zinc.
Inflammatory processes induced by IL-1beta are critical for host defence responses, but are also implicated in disease. Zinc deficiency is a common consequence of, or contributor to, human inflammatory disease. However, the molecular mechanisms through which zinc contributes to inflammatory disease remain largely unknown. We report here that zinc metabolism regulates caspase-1 activation and IL-1beta secretion. One of the endogenous mediators of IL-1beta secretion is adenosine triphosphate, acting via the P2X7-receptor and caspase-1 activation in cells primed with an inflammatory stimulus such as LPS. We show that this process is selectively abolished by a brief pre-treatment with the zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylene diamine (TPEN). These effects on IL-1beta secretion were independent of rapid changes in free zinc within the cell, not a direct effect on caspase-1 activity, and upstream of caspase-1 activation. TPEN did however inhibit the activity of pannexin-1, a hemi-channel critical for adenosine triphosphate and nigericin-induced IL-1beta release. These data provide new insights into the mechanisms of caspase-1 activation and how zinc metabolism contributes to inflammatory mechanisms.
Brough
David
D
Faculty of Life Sciences, University of Manchester, Manchester, UK. david.brough@manchester.ac.uk
Pelegrin
Pablo
P
Rothwell
Nancy J
NJ
D000818:Animals; D020170:Caspase 1 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D017630:Connexins / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D005029:Ethylenediamines / Q000494:pharmacology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000276:immunology* / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D015032:Zinc / Q000276:immunology / Q000378:metabolism*
D017630:Connexins; D005029:Ethylenediamines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; C503631:Panx1 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D020170:Caspase 1; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine