Platelet-activating factor-induced early activation of NF-kappa B plays a crucial role for organ clearance of Candida albicans

In this study, we have investigated the mechanisms underlying organ suscept ibility to candida infection. Infection of BALB/c mice with Candida albican s led to both an early (1-8 h) and late (24-48 h) activation of NF-kappaB i n the organs resistant to C. albicans, including the lung and spleen. In su sceptible organs such as the kidneys, early activation of NF-kappaB was not observed. The kinetics of TNF-alpha mRNA expression paralleled those of NF -kappaB activation in all organs examined. Blocking the effects of endogeno us platelet-activating factor (PAF) by pretreatment with the PAF antagonist BN50739 or antioxidants significantly reduced the early activity of NF-kap paB and TNF-alpha mRNA expression, and increased the recovery of C albicans in the lung and spleen. Importantly, administration of PAF 5 min prior to the infection resulted in the appearance of early activities of NF-kappaB a nd TNF-ce mRNA expression, followed by a nearly complete clearance of the o rganisms in the kidneys. Pretreatment with anti-TNF-alpha Ab resulted in an enhanced susceptibility to C albicans, and the PAF-mediated resistance was abrogated by anti-TNF-alpha in all organs examined. These data indicated t hat endogenously produced PAF in response to C albicans is a key molecule i nvolved in the early activation of NF-kappaB, which, in turn, renders the o rgan resistant to the fungus by promoting the production of anti-candidal p roinflammatory cytokines such as TNF-alpha. Susceptible organs, including t he kidneys, lack the capacity to generate a sufficient PAF-induced early NF -kappaB response. The Journal of Immunology, 2001.