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Processing and Release1
The Dorothy M. Davis Heart and Lung Research Institute and Pulmonary and Critical Care Division, Ohio State University, Columbus, OH 43210
The release of IL-1
is a tightly controlled process that requires induced synthesis of the precursor pro-IL-1 and a second stimulus that initiates cleavage and secretion of mature IL-1. Although ATP as a second stimulus potently promotes IL-1 maturation and release via P2X7 receptor activation, millimolar ATP concentrations are needed. The human cathelicidin-derived peptide LL37 is a potent antimicrobial peptide produced predominantly by neutrophils and epithelial cells. In this study, we report that LL37 stimulation of LPS-primed monocytes leads to maturation and release of IL-1 via the P2X7 receptor. LL37 induces a transient release of ATP, membrane permeability, caspase-1 activation, and IL-1 release without cell cytotoxicity. IL-1 release and cell permeability are suppressed by pretreatment with the P2X7 inhibitors oxidized ATP, KN04, and KN62. In the presence of apyrase, which hydrolyzes ATP to AMP, the effect of LL37 was not altered, indicating that LL37 rather than autocrine ATP is responsible for the activation of the P2X7 receptor. We conclude that endogenous LL37 may promote IL-1 processing and release via direct activation of P2X7 receptors.
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