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Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17

: Schulz, Silke M.; Köhler, Gabriele; Schütze, Nicole; Knauer, Jens; Straubinger, Reinhard K.; Chackerian, Alissa A.; Witte, Ellen; Wolk, Kerstin; Sabat, Robert; Iwakura, Yoichiro; Holscher, Christoph; Müller, Uwe; Kastelein, Robert A.; Alber, Gottfried

The Journal of immunology 181 (2008), Nr.11, S.7891-7901
ISSN: 0022-1767
ISSN: 1048-3233
ISSN: 1047-7381
ISSN: 1550-6606
Fraunhofer IZI ()
Salmonella enterica

IL-12 is essential for protective T cell-mediated immunity against Salmonella infection. To characterize the role of the related cytokine IL-23, wild-type (WT) C57BL/6 and p19 -/-mice were infected systemically with an attenuated strain of Salmonella enterica serovar Enteritidis (S. Enteritidis). IL-23-deficient mice controlled infection with S. Enteritidis similarly as WT mice. Similar IFN-{gamma} production as compared with WT mice, but defective IL-17A and IL-22 production was found in the absence of IL-23. Nevertheless, although IL-23 is required for T cell-dependent cytokine responses, IL-23 is dispensable for protection against S. Enteritidis when IL-12 is present. To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35 -/- mice (lacking IL-12), p35/19 -/- mice (lacking IL-12 and IL-23), p35/40 -/- mice (lacking IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A -/- mice (lacking IL-12 and IL-17A). We found survival of p35 -/-and p35/IL-17A -/- mice, whereas p35/19 -/- and p35/40 -/-mice died within 3–6 wk and developed liver necrosis. This indicates that IL-23, but not homodimeric IL-12p40, is required for protection, which, surprisingly, is independent of IL-17A. Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment. Finally, anti-IL-22 treatment of S. Enteritidis-infected p35 -/- mice resulted in liver necrosis, indicating a central role of IL-22 in hepatocyte protection during salmonellosis. In conclusion, IL-23-dependent IL-22, but not IL-17 production is associated with protection against systemic infection with S. Enteritidis in the absence of IL-12.