Proteolytic Activation of the Interleukin-1β Precursor byCandida albicans

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Abstract
Chronic inflammation rather than invasion is characteristic of some forms of superficial candidiasis such as denture stomatitis. We hypothesized thatCandida albicansmay play a critical role in the pathogenesis of inflammatory lesions observed in chronic candidiasis by activating the proinflammatory cytokine interleukin-1β (IL-1β) from epithelial stores of the precursor. The aim of this study was therefore to demonstrate the proteolytic cleavage and activation of the inactive precursor of IL-1β (pro-IL-1β) byC. albicans. After incubation of either blastospores or hyphae with the inactive precursor, proteolytic cleavage was monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis Western immunoblotting analysis, and the biological activity of the cleavage products was tested in a bioassay. We report here that late-stationary-growth-phase blastospores as well as hyphae ofC. albicans, but not exponentially growing cells, can efficiently cleave pro-IL-1β to yield fragments of molecular masses compatible with mature biologically active IL-1β (17 to 19 kDa). Assays conducted in the presence of selected proteinase inhibitors suggest that the cleavage of pro-IL-1β involves the participation of one or more aspartyl proteinases. Cleavage products showed a dose-dependent IL-1β-like activity in a thymocyte proliferation bioassay, which was inhibited by anti-IL-1β neutralizing antibodies. The present data thus suggest a role forC. albicansproteinases in the activation and maintenance of the inflammatory response at epithelial surfaces.