Defensins block the release but not the processing of IL-1beta and IL-18 from human monocytes

We have previously shown that human defensins can block the release of IL-1beta from LPS-primed human monocytes stimulated with ATP. The objective of this study is to determine whether defensins can inhibit the release IL-1beta and IL-18 from LPS-primed human monocytes stimulated with other inflammasome activators. LPS-activated (20 ng/ml, 2 h), 35S-methionine-labeled (1 h) human monocytes were treated with human defensin HD-5 in the presence or absence of ATP, monosodium urate (MSU), nigericin (Nig) for 90 min. Media and cell-associated fractions were harvested separately. IL-1beta was recovered from each by immunoprecipitation and caspase-1 was examined by western blot analysis. Mature IL-1beta and active caspase-1 were detected in the cytosol fraction from cells treated with HD-5. Thus, HD-5 blocked the release of mature IL-1beta from cells treated with ATP, MSU, or Nig. However, HD-5 did not inhibit ATP-, MSU-, or Nig-induced caspase-1 activation and processing of IL-1beta. In addition, HD-5 also blocked the release of IL-18 from LPS-primed human monocytes stimulated with ATP. To our knowledge, HD-5 is the first known endogenous inhibitor of IL-1beta and IL-18 release. These studies suggest that processing and release of IL-1beta are independent processes.