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

• Published in: The Journal of immunology (1950) 2001-04, Vol.166 (8), p.5139-5144
• Main Authors: Choi, J H, Ko, H M, Kim, J W, Lee, H K, Han, S S, Chun, S B, Im, S Y
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - biosynthesis; Adjuvants, Immunologic - physiology; Animals; Candida albicans; Candida albicans - growth & development; Candida albicans - immunology; Candidiasis - immunology; Candidiasis - metabolism; Candidiasis - microbiology; Disease Susceptibility; Female; Immune Sera - pharmacology; Immunity, Cellular; Immunity, Innate; Injections, Intraperitoneal; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Kidney - microbiology; Lung - immunology; Lung - metabolism; Lung - microbiology; Mice; Mice, Inbred BALB C; NF-kappa B - metabolism; Organ Specificity - immunology; Platelet Activating Factor - administration & dosage; Platelet Activating Factor - biosynthesis; Platelet Activating Factor - physiology; Spleen - immunology; Spleen - metabolism; Spleen - microbiology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.8.5139

In this study, we have investigated the mechanisms underlying organ susceptibility to candida infection. Infection of BALB/c mice with Candida albicans led to both an early (1-8 h) and late (24-48 h) activation of NF-kappaB in the organs resistant to C. albicans, including the lung and spleen. In susceptible 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 endogenous platelet-activating factor (PAF) by pretreatment with the PAF antagonist BN50739 or antioxidants significantly reduced the early activity of NF-kappaB 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 and TNF-alpha mRNA expression, followed by a nearly complete clearance of the organisms 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 that endogenously produced PAF in response to C. albicans is a key molecule involved in the early activation of NF-kappaB, which, in turn, renders the organ resistant to the fungus by promoting the production of anti-candidal proinflammatory cytokines such as TNF-alpha. Susceptible organs, including the kidneys, lack the capacity to generate a sufficient PAF-induced early NF-kappaB response.