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 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.
Choi
J H
JH
Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Kwangju, Korea.
Ko
H M
HM
Kim
J W
JW
Lee
H K
HK
Han
S S
SS
Chun
S B
SB
Im
S Y
SY
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D002176:Candida albicans / Q000254:growth & development* / Q000276:immunology; D002177:Candidiasis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D004198:Disease Susceptibility; D005260:Female; D007106:Immune Sera / Q000494:pharmacology; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009928:Organ Specificity / Q000276:immunology; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology
D000276:Adjuvants, Immunologic; D007106:Immune Sera; D016328:NF-kappa B; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha