Interleukin 18 restores defective Th1 immunity to Candida albicans in caspase 1-deficient mice

Caspase 1, formerly designated interleukin 1 beta (IL-1 beta)-converting en zyme, processes pro-IL-1 beta and pro-IL-18 to yield active cytokines that play a pivotal role in inflammation and cell activation. We show here the e ffect of caspase 1 deficiency on the inflammatory and adaptive immune respo nses to the fungus Candida albicans. Caspase 1 deficiency did not affect su sceptibility to primary systemic infection with the fungus, as revealed by survival and fungal growth. However, Th1-mediated resistance to reinfection was greatly impaired in caspase 1-deficient mice, and this correlated with low-level production of IL-12 and gamma interferon. Early in infection, pr oduction of these cytokines and that of tumor necrosis factor alpha, IL-6, and, interestingly, IL-1 beta occurred normally in caspase 1-deficient mice , while that of IL-18 was severely impaired. Exogenous administration of IL -18, more than IL-12, restored the Th1-mediated resistance to the infection . We conclude that, while caspase 1 is not indispensable for release of mat ure IL-1 beta in candidiasis, the caspase 1-dependent production of IL-18 m ay represent an important and novel pathway for the expression of sustained Th1 reactivity to the fungus.