Happel Kyle I, Lockhart Euan A, Mason Carol M, Porretta Elizabeth, Keoshkerian Elizabeth, Odden Anthony R, Nelson Steve, Ramsay Alistair J
Section of Pulmonary/Critical Care Medicine, Louisiana State University Health Sciences Center, Suite 3205, 1901 Perdido St., New Orleans, LA 70112, USA.
Infect Immun. 2005 Sep;73(9):5782-8. doi: 10.1128/IAI.73.9.5782-5788.2005.
Interleukin-23 (IL-23) is a heterodimeric cytokine that shares IL-12 p40 but contains a unique p19 subunit similar to IL-12 p35. Previous studies indicate a greater importance for intact IL-12/23 p40 expression than IL-12 p35 for immunity against Mycobacterium tuberculosis, suggesting a role for IL-23 in host defense. The effects of IL-23 on the outcome of pulmonary infection with M. tuberculosis have not been described. Here, we show that local delivery of replication-defective adenovirus vectors encoding IL-23 (AdIL-23) greatly stimulated expression of both gamma interferon (IFN-gamma) and IL-17 in lung tissues of otherwise normal mice. When given 72 h prior to infection with M. tuberculosis, AdIL-23 significantly reduced the bacterial burden at 14, 21, and 28 days. Markedly lower levels of lung inflammation were observed at 28 days than in control mice pretreated with control adenovirus (AdNull) or vehicle controls. AdIL-23 pretreatment resulted in increased numbers of CD4(+) CD25(+) activated T cells in lungs and draining lymph nodes compared to control groups and more CD4(+) T cells bearing surface memory markers in lung lymph nodes. IL-23 gene delivery also significantly enhanced host anti-mycobacterial T-cell responses, as shown by elevated levels of IFN-gamma and IL-17 secreted in vitro following restimulation with M. tuberculosis purified protein derivative. Overall, our data show that transient IL-23 gene delivery in the lung is well tolerated, and they provide the initial demonstration that this factor controls mycobacterial growth while augmenting early pulmonary T-cell immunity.
白细胞介素-23（IL-23）是一种异二聚体细胞因子，它与IL-12 p40共享，但包含一个与IL-12 p35相似的独特p19亚基。先前的研究表明，完整的IL-12/23 p40表达比IL-12 p35对抵抗结核分枝杆菌的免疫力更为重要，这表明IL-23在宿主防御中发挥作用。IL-23对结核分枝杆菌肺部感染结果的影响尚未见报道。在此，我们表明，局部递送编码IL-23的复制缺陷型腺病毒载体（AdIL-23）可极大地刺激正常小鼠肺组织中γ干扰素（IFN-γ）和IL-17的表达。在感染结核分枝杆菌前72小时给予AdIL-23，可在第14、21和28天显著降低细菌负荷。与用对照腺病毒（AdNull）或载体对照预处理的对照小鼠相比，在第28天观察到的肺部炎症水平明显较低。与对照组相比，AdIL-23预处理导致肺和引流淋巴结中CD4(+) CD25(+)活化T细胞数量增加，肺淋巴结中带有表面记忆标记的CD4(+) T细胞更多。如用结核分枝杆菌纯化蛋白衍生物再次刺激后体外分泌的IFN-γ和IL-17水平升高所示，IL-23基因递送也显著增强了宿主抗分枝杆菌T细胞反应。总体而言，我们的数据表明，肺中短暂的IL-23基因递送耐受性良好，并且首次证明该因子在增强早期肺部T细胞免疫的同时控制分枝杆菌生长。
