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.