Cytokine networking in lungs of immunocompetent mice in response to inhaled Aspergillus fumigatus
Cytokine networking in lungs of immunocompetent mice in response to inhaled Aspergillus fumigatus
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DOI：
10.1128/iai.69.3.1554-1560.2001
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发表时间：
2001-03-01
影响因子：
3.1
通讯作者：
O'Garra, A
中科院分区：
文献类型：
--
作者：
Brieland, JK;Jackson, C;O'Garra, A
使用免疫活性Crl：CF-1小鼠的原发性肺曲霉病小鼠模型评估肺中响应于吸入烟曲霉菌的细胞因子网络。吸入有毒的A.烟曲霉菌（6 × 10（6）CFU）导致在支气管肺泡灌洗液和/或肺组织中诱导白细胞介素18（IL-18）、肿瘤坏死因子α（TNF-α）、IL-12和γ干扰素（IFN-γ）蛋白。免疫反应性IL-18的诱导先于TNF-α蛋白的诱导，TNF-α蛋白的诱导先于免疫反应性IL-12和IFN-γ的诱导。感染肺组织的实时逆转录酶（RT）PCR分析表明，IL-18蛋白的诱导也先于肺TNF-α、IL-12和IFN-γ mRNA的诱导。随后用针对IL-18受体（抗IL-18 R MAb）、TNF-α（抗TNF-α MAb）、IL-12（抗IL-12 MAb）和/或IFN-γ（抗IFN-γ MAb）的精氨酸特异性中和单克隆抗体（MAb）处理小鼠，观察对肺内细胞因子活性和A.在感染的肺匀浆中评估烟曲霉。同时中和IL-12和IL-18导致免疫反应性TNF-α水平降低，而单独中和IL-18、TNF-α或IL-12或IL-18和IL-12一起导致免疫反应性IFN-γ水平降低。IL-12和IL-18的同时中和或TNF-α单独中和或TNF-α与IL-12、IL-18或IFN-γ联合中和也导致A.肺组织中的烟曲霉菌CFU。总之，这些结果表明内源性IL-18、IL-12和TNF-α通过其对肺内细胞因子活性和A.烟曲霉在宿主防御原发性肺曲霉病中起关键作用。
Cytokine networking in the lung in response to inhaled Aspergillus fumigatus was assessed using a murine model of primary pulmonary aspergillosis in immunocompetent Crl:CF-1 mice. Inhalation of virulent A. fumigatus (6 x 10(6) CFU) resulted in the induction of interleukin 18 (IL-18), tumor necrosis factor alpha (TNF-alpha), IL-12, and gamma interferon (IFN-gamma) protein in bronchoalveolar lavage fluid and/or lung tissue. Induction of immunoreactive IL-18 preceded induction of TNF-alpha protein, which preceded induction of immunoreactive IL-12 and IFN-gamma. Real-time reverse transcriptase (RT) PCR analysis of infected lung tissue demonstrated that induction of IL-18 protein also preceded induction of pulmonary TNF-alpha, IL-12, and IFN-gamma mRNAs. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to the IL-18 receptor (anti-IL-18R MAb), TNF-alpha (anti-TNF-alpha MAb), IL-12 (anti-IL-12 MAb), and/or IFN-gamma (anti-IFN-gamma MAb), and effects on intrapulmonary cytokine activity and growth of A. fumigatus were assessed in infected lung homogenates. Simultaneous neutralization of IL-12 and IL-18 resulted in decreased levels of immunoreactive TNF-alpha, while neutralization of IL-18, TNF-alpha, or IL-12 alone or of IL-18 and IL-12 together resulted in decreased levels of immunoreactive IFN-gamma. Simultaneous neutralization of IL-12 and IL-18 or neutralization of TNF-a alone or in combination with IL-12, IL-18, or IFN-gamma also resulted in a significant increase in A. fumigatus CFU in lung tissue. Taken together, these results demonstrate that endogenous IL-18, IL-12, and TNF-alpha, through their modulatory effects on both intrapulmonary cytokine activity and growth of A. fumigatus, play key roles in host defense against primary pulmonary aspergillosis.