In the healthy intestinal mucosa, homeostasis between the immune system and commensal microflora prevents detrimental inflammatory responses. Infection with acute enteropathogens such as Salmonella enterica serovar Typhimurium disturbs this homeostasis and triggers inflammation, but the underlying mechanisms are poorly understood. We found that bacterial delivery or ectopic expression of the S. Typhimurium type III effector protein SopE, a known activator of host cellular Rho GTPases, led to proinflammatory caspase-1 activation and consequent maturation and secretion of the cytokine IL-1beta. In vivo, SopE triggered mucosal inflammation in wild-type but not caspase-1(-/-), IL-1R(-/-), or IL-18(-/-) mice. Bone marrow chimeras indicated that caspase-1 was more important in stromal cells, most likely enterocytes, than in bone marrow-derived cells. SopE-mediated caspase-1 activation in vitro was mediated by cellular Rho GTPases Rac-1 and Cdc42. These findings implicate SopE-driven Rho GTPase-mediated caspase-1 activation in stromal cells as a mechanism eliciting mucosal inflammation during S. Typhimurium infection.

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Interleukin-1b (IL-1b) is a cytokine that shares with tumor necrosis factor (TNF) the ability to initiate largely similar signaling pathways, leading to proinflammatory gene expression. In contrast to TNF, however, IL-1b is not believed to induce tumor cell death. Here we demonstrate that prolonged treatment with IL-1b, in combination with interferon-c (IFNc), is cytotoxic for L929 tumor cells. IL-1b/IFNc-induced cytotoxicity requires only minimal amounts of IL-1b and shows morphological features of necrosis. Although TNF induces a similar response, we could exclude a contribution of endogenous TNF production in the effect of IL-1b/IFNc. Cell death in response to IL-1b/IFNc is independent of caspases, but requires the IL-1b/IFNc-induced production of inducible nitric oxide synthase (iNOS) and NO. Moreover, necrosis and iNOS/NO production could be prevented by treatment of the cells with a p38 mitogen activated protein kinase (p38MAPK) or IjB kinase b inhibitor. Altogether, these findings demonstrate that prolonged exposure to IL-1b plus IFNc induces L929 tumor cell necrosis, via a p38MAPK and nuclear factorjB (NF-jB)-dependent signaling pathway, leading to the expression of iNOS and the production of toxic NO levels.