Caspase-1 activation of IL-1 beta and IL-18 are essential for Shigella flexneri-induced inflammation

Caspases are intracellular proteases that mediate mammalian cell apoptosis. Caspase-1 (Casp-1) is a unique caspase because it activates the proinflamm atory cytokines interleukin (Il)-1 beta and IL-18. Shigella flexneri, the e tiological agent of bacillary dysentery, induces macrophage apoptosis, whic h requires Casp-1 and results in the release of mature IL-1 beta and IL-18. Here we show that casp-1(-/-) mice infected with S. flexneri do not develo p the acute inflammation characteristic of shigellosis and are unable to re solve the bacterial infection. Using casp-1(-/-) mice supplemented with rec ombinant cytokines and experiments with IL-1 beta(-/-) and IL-18(-/-) mice, we show that IL-1 beta and IL-18 are both required to mediate inflammation in S. flexneri infections. Together, these data demonstrate the importance of Casp-1 in acute inflammation and show the different roles of its substr ates, IL-1 beta and IL-18, in this response.