Caspase-1 activation of IL-1beta 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 proinflammatory cytokines interleukin (IL)-1beta and IL-18. Shigella flexneri, the etiological agent of bacillary dysentery, induces macrophage apoptosis, which requires Casp-1 and results in the release of mature IL-1beta and IL-18. Here we show that casp-1(-/-) mice infected with S. flexneri do not develop the acute inflammation characteristic of shigellosis and are unable to resolve the bacterial infection. Using casp-1(-/-) mice supplemented with recombinant cytokines and experiments with IL-1beta(-/-) and IL-18(-/-) mice, we show that IL-1beta 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 substrates, IL-1beta and IL-18, in this response.
Sansonetti
P J
PJ
Unité de Pathogénie Microbienne Moléculaire, INSERM U389, Institut Pasteur, Paris, France.
Phalipon
A
A
Arondel
J
J
Thirumalai
K
K
Banerjee
S
S
Akira
S
S
Takeda
K
K
Zychlinsky
A
A
D000818:Animals; D020170:Caspase 1 / Q000276:immunology*; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D051379:Mice; D012763:Shigella flexneri; D013379:Substrate Specificity / Q000276:immunology
D007375:Interleukin-1; D020382:Interleukin-18; D020170:Caspase 1