Abstract
Inflammatory processes induced by IL-1β 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-1β secretion. One of the endogenous mediators of IL-1β 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-1β 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-1β release. These data provide new insights into the mechanisms of caspase-1 activation and how zinc metabolism contributes to inflammatory mechanisms.
Highlights
The pro-inflammatory cytokine IL-1b is a key mediator of host-defence responses, which contributes to the pathogenesis of diverse diseases [1]
We first tested the hypothesis that zinc contributes to caspase-1dependent pro-IL-1b cleavage and mature IL-1b release by exposing LPS-primed (1 mg/mL, 2 h) mouse peritoneal macrophages to the zinc chelator N,N,N0,N0-tetrakis-(2-pyridylmethyl) ethylene diamine (TPEN) for 15 min prior to 10 min incubation with 5 mM adenosine triphosphate (ATP)
In the experiment described in the previous paragraph, macrophages were incubated with ATP for 10 min
Summary
The pro-inflammatory cytokine IL-1b is a key mediator of host-defence responses, which contributes to the pathogenesis of diverse diseases [1]. Its expression and release are controlled at multiple levels by cells of the innate immune system and this currently constitutes an intense area of research. IL-1b is expressed in response to stimulation of pattern recognition receptors of the TLR family, as an inactive 31 kDa precursor pro-IL-1b [1], which is not released from intact cells. Pro-IL-1b is expressed without a signal sequence [2] and is translated in the cytoplasm of macrophages stimulated with bacterial endotoxin (LPS) [3]. Cells expressing pro-IL-1b require a second stimulus to activate the protease caspase-1 that cleaves pro-IL-1b to IL-1b, which is secreted. A number of triggers for caspase-1 activation have been identified; all activate cytosolic pattern recognition receptors and induce the assembly of inflammasome complexes that result in
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
