Impairment of p38 MAPK-mediated cytosolic phospholipase A2 activation in the kidneys is associated with pathogenicity of Candida albicans

Abstract

In studying the mechanisms underlying the susceptibility of the kidney to candidal infection, we previously reported that the reduced production of cytokines [i.e. tumour necrosis factor-α (TNF-α)] via platelet-activating factor (PAF)-induced activation of nuclear factor-κB (NF-κB) renders the organ susceptible to the fungal burden. In this study, we investigated the possibility that pathogenic Candida albicans may evade clearance and perhaps even multiply by inhibiting elements in the signalling pathway that lead to the production of TNF-α. The fungal burden of pathogenic C. albicans in the kidneys was 104-105-fold higher than that of a non-pathogenic strain. PAF-induced early activation of NF-κB and TNF-α mRNA expression were both observed in the kidneys of mice infected with non-pathogenic strains of C. albicans, but not in mice infected with pathogenic strains. Impairment of PAF-mediated early NF-κB activation following infection with pathogenic C. albicans was associated with the prevention of activation of the enzyme cytosolic phospholipase A2 (cPLA2) as well as the upstream pathway of cPLA2, p38 mitogen-activated protein kinase. Collectively, these findings indicate that C. albicans exerts its pathogenicity through impairing the production of anticandidal cytokines by preventing cPLA2 activity. This novel mechanism provides insight into understanding pathogenic C. albicans and perhaps identifies a target for its treatment. © 2007 Blackwell Publishing Ltd.