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* Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany;
Department of Drug Safety and Metabolism, Schering-Plough Research Institute, Lafayette, NJ 07848;
Institute of Neuropathology, Medical Faculty, University of Cologne, Cologne, Germany;
Gerhard Domagk Institute of Pathology, University of Muenster, Muenster, Germany;
¶ Experimental Pathology and Pharmacology, DNAX Research, Palo Alto, CA 94304; and
|| Discovery Research, DNAX Research, Palo Alto, CA 94304
IL-23, a heterodimeric cytokine composed of the p40 subunit of IL-12 and a novel p19 subunit, has been shown to be a key player in models of autoimmune chronic inflammation. To investigate the role of IL-23 in host resistance during chronic fungal infection, wild-type, IL-12- (IL-12p35–/–), IL-23- (IL-23p19–/–), and IL-12/IL-23- (p40-deficient) deficient mice on a C57BL/6 background were infected with Cryptococcus neoformans. Following infection, p40-deficient mice demonstrated higher mortality than IL-12p35–/– mice. Reconstitution of p40-deficient mice with rIL-23 prolonged their survival to levels similar to IL-12p35–/– mice. IL-23p19–/– mice showed a moderately reduced survival time and delayed fungal clearance in the liver. Although IFN-
production was similar in wild-type and IL-23p19–/– mice, production of IL-17 was strongly impaired in the latter. IL-23p19–/– mice produced fewer hepatic granulomata relative to organ burden and showed defective recruitment of mononuclear cells to the brain. Moreover, activation of microglia cells and expression of IL-1
, IL-6, and MCP-1 in the brain was impaired. These results show that IL-23 complements the more dominant role of IL-12 in protection against a chronic fungal infection by an enhanced inflammatory cell response and distinct cytokine regulation.
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