Clara cells impact the pulmonary innate immune response to LPS
Clara cells impact the pulmonary innate immune response to LPS
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DOI：
10.1152/ajplung.00024.2007
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发表时间：
2007-08-01
影响因子：
4.9
通讯作者：
Senior, Robert M.
中科院分区：
文献类型：
--
作者：
Elizur, Arnon;Adair-Kirk, Tracy L.;Senior, Robert M.
气道上皮细胞响应 LPS 分泌促炎介质，但主要的非纤毛细支气管上皮细胞（具体而言，克拉拉细胞）产生的细胞因子尚不清楚。为了研究 LPS 反应下 Clara 细胞细胞因子的产生，我们使用了转化的小鼠 Clara 细胞系 C22 和从 C57B1/6 小鼠中分离的 Clara 细胞。用 LPS 刺激两种细胞类型都会导致角质形成细胞衍生的趋化因子 (KC) 和单核细胞趋化蛋白-1 的显着上调，但不会诱导 TNF-α 的产生。为了确定 LPS 是否在体内诱导 Clara 细胞产生细胞因子，将 LPS 注入小鼠气管内。通过原位杂交测定，LPS 给药后 2 小时，Clara 细胞、肺泡 2 型细胞和肺泡巨噬细胞表达 KC。 TNF-α虽然不在气道上皮细胞中表达，但主要在肺泡巨噬细胞中表达以响应LPS。为了评估 Clara 细胞在 LPS 早期反应中对肺部 KC 和 TNF-α 产生的影响，在 LPS 刺激之前用萘处理小鼠以选择性诱导 Clara 细胞损伤。 LPS 刺激后，与媒介物处理的小鼠相比，萘处理的小鼠气道和肺周围的 KC 表达以及支气管肺泡灌洗液中的 KC 和 TNF-α 水平显着降低。此外，C22 细胞和 RAW264.7 巨噬细胞的 Transwell 共培养表明，C22 细胞响应 LPS 释放可溶性因子，增强巨噬细胞 TNF-α 的产生。这些结果表明 Clara 细胞合成细胞因子并调节肺对 LPS 的先天免疫反应。
Airway epithelial cells secrete proinflammatory mediators in response to LPS, but cytokine production by a prominent nonciliated bronchiolar epithelial cell, the Clara cell, specifically, is unknown. To investigate Clara cell cytokine production in response to LPS, we used a transformed murine Clara cell line, C22, and isolated Clara cells from C57B1/6 mice. Stimulation of both cell types with LPS resulted in significant upregulation of keratinocyte-derived chemokine (KC) and monocyte chemoattractant protein-1, but did not induce TNF-alpha production. To determine whether LPS induces cytokine production by Clara cells in vivo, LPS was instilled intratracheally into mice. KC was expressed by Clara cells, alveolar type 2 cells, and alveolar macrophages, 2 h after LPS administration, as determined by in situ hybridization. TNF-alpha, although not expressed in airway epithelial cells, was expressed primarily in alveolar macrophages in response to LPS. To assess the impact of Clara cells on KC and TNF-alpha production in the lung in the early response to LPS, mice were treated with naphthalene to selectively induce Clara cell injury before LPS stimulation. KC expression in the airways and the lung periphery, and KC and TNF-alpha levels in the bronchoalveolar lavage fluid, were significantly reduced in naphthalene-treated vs. vehicle-treated mice after LPS stimulation. Furthermore, transwell cocultures of C22 cells and RAW264.7 macrophages indicated that C22 cells released a soluble factor(s) in response to LPS that enhanced macrophage production of TNF-alpha. These results indicate that Clara cells elaborate cytokines and modulate the lung innate immune response to LPS.