IL-23 Enhances the Inflammatory Cell Response in Cryptococcus neoformans Infection and Induces a Cytokine Pattern Distinct from IL-12

• Published in: Journal of Immunology Vol. 176; no. 2; pp. 1098 - 1106
• Main Authors: Kleinschek, Melanie A, Muller, Uwe, Brodie, Scott J, Stenzel, Werner, Kohler, Gabriele, Blumenschein, Wendy M, Straubinger, Reinhard K, McClanahan, Terrill, Kastelein, Robert A, Alber, Gottfried
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.01.2006
• Subjects: Animals; Brain - immunology; Brain - pathology; Cryptococcus neoformans; Cytokines - biosynthesis; Inflammation - immunology; Interleukin-12 - biosynthesis; Interleukin-12 - deficiency; Interleukin-12 - genetics; Interleukin-17 - biosynthesis; Interleukin-23; Interleukin-23 Subunit p19; Interleukins - deficiency; Interleukins - genetics; Interleukins - pharmacology; Interleukins - physiology; Meningitis, Cryptococcal - immunology; Meningitis, Cryptococcal - pathology; Meningitis, Cryptococcal - prevention & control; Mice; Mice, Inbred C57BL; Mice, Knockout; Recombinant Proteins - pharmacology; Th1 Cells - immunology; Th2 Cells - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.2.1098

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-gamma 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-1beta, 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.