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* Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany;
Gerhard Domagk Institute of Pathology, University of Münster, Münster, Germany;
Discovery Research, Schering-Plough Biopharma, Palo Alto, CA 94304;
Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University Hospital Charité, Berlin, Germany;
¶ University of Tokyo, Tokyo, Japan; and
|| Research Center Borstel, Borstel, Germany
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-
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.
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1 This work was supported by Research Grant Al 371/3-3 from the Deutsche Forschungsgemeinschaft (to G.A.) and Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie Grant EXC306 "Inflammation at Interfaces" (to C.H.).
2 Address correspondence and reprint requests to Dr. Gottfried Alber, Institute of Immunology, College of Veterinary Medicine, University of Leipzig, An den Tier-kliniken 11, 04103 Leipzig, Germany. E-mail address: alber{at}rz.uni-leipzig.de
3 Abbreviations used in this paper: S. Enteritidis, Salmonella enterica serovar Enteritidis; dpi, days postinfection; hk, heat killed; HPRT, hypoxanthine phosphoribosyltransferase; NACE, naphthol AS-D-chloracetate; PMN, polymorphonuclear cell; WT, wild type.
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  S. Siegemund, N. Schutze, S. Schulz, K. Wolk, K. Nasilowska, R. K. Straubinger, R. Sabat, and G. Alber Differential IL-23 requirement for IL-22 and IL-17A production during innate immunity against Salmonella enterica serovar Enteritidis Int. Immunol., May 1, 2009; 21(5): 555 - 565. [Abstract] [Full Text] [PDF]
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