In humans and other primates, 1,25(OH)2vitamin D3 regulates the expression of the cathelicidin antimicrobial peptide (CAMP) gene via toll-like receptor (TLR) signaling that activates the vitamin D pathway. Mice and other mammals lack the vitamin D response element (VDRE) in their CAMP promoters. To elucidate the biological importance of this pathway, we generated transgenic mice that carry a genomic DNA fragment encompassing the entire human CAMP gene and crossed them with Camp knockout (KO) mice. We observed expression of the human transgene in various tissues and innate immune cells. However, in mouse CAMP transgenic macrophages, TLR activation in the presence of 25(OH)D3 did not induce expression of either CAMP or CYP27B1 as would normally occur in human macrophages, reinforcing important species differences in the actions of vitamin D. Transgenic mice did show increased resistance to colonization by Salmonella typhimurium in the gut. Furthermore, the human CAMP gene restored wound healing in the skin of Camp KO mice. Topical application of 1,25(OH)2vitamin D3 to the skin of CAMP transgenic mice induced CAMP expression and increased killing of Staphylococcus aureus in a wound infection model. Our model can help elucidate the biological importance of the vitamin D-cathelicidin pathway in both pathogenic and non-pathogenic states.

中文翻译：

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维生素 D 诱导的人抗菌肽基因表达的小鼠模型。


在人类和其他灵长类动物中，1,25(OH)2 维生素 D3 通过激活维生素 D 途径的 Toll 样受体 (TLR) 信号传导调节抗菌肽 (CAMP) 基因的表达。小鼠和其他哺乳动物的 CAMP 启动子中缺乏维生素 D 反应元件 (VDRE)。为了阐明该途径的生物学重要性，我们培育了携带包含整个人类 CAMP 基因的基因组 DNA 片段的转基因小鼠，并将其与 Camp 敲除 (KO) 小鼠杂交。我们观察了人类转基因在各种组织和先天免疫细胞中的表达。然而，在小鼠 CAMP 转基因巨噬细胞中，25(OH)D3 存在下的 TLR 激活不会像人类巨噬细胞中通常发生的那样诱导 CAMP 或 CYP27B1 的表达，从而强化了维生素 D 作用的重要物种差异。显示出对肠道中鼠伤寒沙门氏菌定植的抵抗力增强。此外，人类 CAMP 基因恢复了 Camp KO 小鼠皮肤的伤口愈合。在伤口感染模型中，将 1,25(OH)2 维生素 D3 局部涂抹到 CAMP 转基因小鼠的皮肤上可诱导 CAMP 表达，并增加对金黄色葡萄球菌的杀灭作用。我们的模型可以帮助阐明维生素 D-cathelicidin 途径在致病和非致病状态下的生物学重要性。