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
Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
J Immunol. 2008 Dec 1;181(11):7891-901. doi: 10.4049/jimmunol.181.11.7891.
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.
白细胞介素-12对于保护性T细胞介导的抗沙门氏菌感染免疫至关重要。为了阐明相关细胞因子白细胞介素-23的作用，用肠炎沙门氏菌肠炎血清型（肠炎沙门氏菌）减毒株对野生型（WT）C57BL/6和p19(-/-)小鼠进行全身感染。白细胞介素-23缺陷型小鼠与野生型小鼠类似地控制了肠炎沙门氏菌感染。在缺乏白细胞介素-23的情况下，与野生型小鼠相比，干扰素-γ产生相似，但白细胞介素-17A和白细胞介素-22产生存在缺陷。然而，尽管白细胞介素-23是T细胞依赖性细胞因子反应所必需的，但当存在白细胞介素-12时，白细胞介素-23对于抗肠炎沙门氏菌感染的保护作用是可有可无的。为了分析在缺乏白细胞介素-12的情况下白细胞介素-23的作用，将低剂量的肠炎沙门氏菌给予p35(-/-)小鼠（缺乏白细胞介素-12）、p35/19(-/-)小鼠（缺乏白细胞介素-12和白细胞介素-23）、p35/40(-/-)小鼠（缺乏白细胞介素-12、白细胞介素-23和同二聚体白细胞介素-12p40）或p35/白细胞介素-17A(-/-)小鼠（缺乏白细胞介素-12和白细胞介素-17A）。我们发现p35(-/-)和p35/白细胞介素-17A(-/-)小鼠存活，而p35/19(-/-)和p35/40(-/-)小鼠在3-6周内死亡并出现肝坏死。这表明白细胞介素-23而非同二聚体白细胞介素-12p40是保护所必需的，令人惊讶的是，这与白细胞介素-17A无关。此外，保护作用与白细胞介素-22相关，但与白细胞介素-17F或白细胞介素-21表达或中性粒细胞募集无关。最后，对肠炎沙门氏菌感染的p35(-/-)小鼠进行抗白细胞介素-22治疗导致肝坏死，表明白细胞介素-22在沙门氏菌病期间肝细胞保护中起核心作用。总之，在缺乏白细胞介素-12的情况下，白细胞介素-23依赖性白细胞介素-22而非白细胞介素-17的产生与抗肠炎沙门氏菌全身感染的保护作用相关。
