Cytotoxicity and interleukin-1β processing following Shigella flexneri infection of human monocyte-derived dendritic cells

Abstract

Shigella flexneri infection of macrophages (Mφ) leads to activation of caspase-1 by the lpaB virulence factor, which induces rapid cell death and release of mature IL-1β. Here we show that S. flexneri infection of human monocyte-derived dendritic cells (DC) also results in rapid IpaB-dependent death. Cytotoxicity is only partially blocked by the caspase-1 inhibitor YVAD, but completely blocked by the pan-caspase inhibitor z-VAD. Cytotoxicity is also partially blocked by glycine without affecting caspase-1-dependent IL-1β processing, and treatment with glycine and YVAD completely blocks cytotoxicity, implying that glycine inhibits a caspase-1-independent cytotoxic mechanism. S. flexneri infection of LPS-pre-treated DC and Mφ results in comparable release of mature IL-1β, although DC release significantly less IL-18 than Mφ. IL-1β release from infected DC occurs within 3 h of the initial LPS pre-stimulation signal, implying that infection of DC will contribute towards induction of the early inflammatory response. The rapid death of DC during the early stages of shigellosis is likely to have adverse consequences for generation of adaptive immunity.