IL-23 enhances host Defense against vaccinia virus infection via a mechanism partly involving IL-17
IL-23 enhances host Defense against vaccinia virus infection via a mechanism partly involving IL-17
复制标题
DOI：
10.4049/jimmunol.179.6.3917
复制
发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Matsui, Masanori
中科院分区：
文献类型：
--
作者：
Kohyama, Shunsuke;Ohno, Satoshi;Matsui, Masanori
为了研究IL-23在病毒感染中的作用，我们设计了表达IL-12（VV-IL-12）和表达IL-23（VV-IL-23）的重组牛痘病毒（VV）。我们发现VV-IL-23在BALB/c小鼠中的毒性低于野生型VV（VV-WT），表明IL-23增强对VV的抗性。VV-IL-23感染小鼠的VV特异性CTL活性略高于VV-WT接种小鼠的活性，尽管抗病毒Ab产生和NK活性没有增加。IL-12/23 p40缺陷型小鼠在VV-IL-23感染后存活，表明IL-23独立于IL-12促进VV抗性。IL-23介导的抗性的机制不同于IL-12调节的抗性的机制，因为IFN-γ缺陷型小鼠不消除VV-IL-12，但消除VV-IL-23。这些数据表明IFN-γ对于IL-12介导的抗性是必需的，但是对于IL-23调节的抗性是必需的。由于IL-17是IL-23调节的细菌抗性的关键，我们假设IL-17参与VV抗性。用抗IL-17 mAb治疗导致VV-IL-23感染的IFN-γ缺陷小鼠中病毒滴度显著增加。此外，在BALB/c小鼠中，VV-IL-17的毒性低于VV-WT，并且IL-17缺陷小鼠对VV-WT比对照小鼠更敏感。然而，用抗IL-17 mAb中和的效果是有限的，并且IL-17缺陷型小鼠在用VV-IL-23感染后存活。综上所述，这些数据表明，IL-23/IL-17轴在IL-23介导的VV抗性中起一定但次显性的作用。揭示IL-23调节的抗性中的替代途径可能提供对抗感染性病原体而没有自身免疫副作用的新策略。
To investigate roles of IL-23 in viral infection, we have engineered recombinant vaccinia virus (VV) expressing IL-12 (VV-IL-12) and expressing IL-23 (VV-IL-23). We found VV-IL-23 was less virulent in BALB/c mice than wild-type VV (VV-WT), indicating that IL-23 enhances resistance to VV. VV-specific CTL activity in VV-IL-23-infected mice was slightly higher than activity in VV-WT-inoculated mice, although antiviral Ab production and NK activity were not increased. IL-12/23p40-deficient mice survived the infection with VV-IL-23, indicating that IL-23 promotes VV resistance independently of IL-12. The mechanism of the IL-23-mediated resistance was distinct from that of the IL-12-regulated resistance because IFN-gamma-deficient mice did not eliminate VV-IL-12, but did eradicate VV-IL-23. These data indicate that IFN-gamma is essential for the IL-12-mediated resistance, but dispensable for the IL-23-regulated resistance. Because IL-17 is a key in the IL-23-regulated resistance to bacteria, we hypothesized an involvement of IL-17 in the resistance to VV. Treatment with an anti-IL-17 mAb resulted in a significant increase of viral titers in VV-IL-23-infected IFN-gamma-deficient mice. In addition, VV-IL-17 was less virulent than VV-WT in BALB/c mice, and IL-17-deficient mice were more sensitive to VV-WT than control mice. However, the effect of neutralization with an anti-IL-17 mAb was limited, and IL-17-deficient mice survived the infection with VV-IL-23. Taken together, these data suggest that the IL-23/IL-17 axis plays a certain but subdominant role in the IL-23-mediated resistance to VV. Unveiling of an alternative pathway in the IL-23-regulated resistance might provide a novel strategy against infectious pathogens without side effects of autoimmunity.