IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12.
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.
Kleinschek
Melanie A
MA
Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
Muller
Uwe
U
Brodie
Scott J
SJ
Stenzel
Werner
W
Kohler
Gabriele
G
Blumenschein
Wendy M
WM
Straubinger
Reinhard K
RK
McClanahan
Terrill
T
Kastelein
Robert A
RA
Alber
Gottfried
G
D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis*; D007249:Inflammation / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D016919:Meningitis, Cryptococcal / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; C508841:Il23a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D011994:Recombinant Proteins; D018664:Interleukin-12