Secreted hCLCA1 Is a Signaling Molecule That Activates Airway Macrophages
Secreted hCLCA1 Is a Signaling Molecule That Activates Airway Macrophages
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DOI：
10.1371/journal.pone.0083130
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发表时间：
2013-12-12
期刊：
影响因子：
3.7
通讯作者：
Loewen, Matthew E.
中科院分区：
文献类型：
--
作者：
Ching, John C. H.;Lobanova, Liubov;Loewen, Matthew E.
CLCA基因家族产生分泌和膜相关蛋白，其调节离子通道功能，驱动粘液产生，并且对气道炎症具有知之甚少的多效性作用。在气道炎症中主要上调的人CLCA直系同源物是hCLCA 1。在这里，我们表明，这种蛋白质可以激活气道巨噬细胞，诱导他们表达细胞因子，并承担在气道炎症的关键作用。在U-937气道巨噬细胞-单核细胞细胞系中，来自异源表达hCLCA 1的HEK 293细胞的条件培养基（含或不含胎牛血清）增加了促炎细胞因子（IL-1 β、IL-6、TNF-α和IL-8）的水平。这种作用不依赖于hCLCA 1的金属蛋白酶结构域。原代猪肺泡巨噬细胞被类似地激活，证明该效应不是细胞系依赖性的。类似地，在类似于100 pg/mL的生理相关浓度下的免疫纯化的hCLCA 1能够激活巨噬细胞并诱导促炎反应。这种细胞因子应答随着免疫纯化的hCLCA 1浓度的增加而增加。这些发现证明了hCLCA 1作为信号分子和激活巨噬细胞的能力，巨噬细胞是气道炎症的中枢调节因子。
The CLCA gene family produces both secreted and membrane-associated proteins that modulate ion-channel function, drive mucus production and have a poorly understood pleiotropic effect on airway inflammation. The primary up-regulated human CLCA ortholog in airway inflammation is hCLCA1. Here we show that this protein can activate airway macrophages, inducing them to express cytokines and to undertake a pivotal role in airway inflammation. In a U-937 airway macrophage-monocyte cell line, conditioned media from HEK 293 cells heterologously expressing hCLCA1 (with or without fetal bovine serum) increased the levels of pro-inflammatory cytokines (IL-1 beta, IL-6, TNF-alpha and IL-8). This effect was independent of the metalloprotease domain of hCLCA1. Primary porcine alveolar macrophages were similarly activated, demonstrating the effect was not cell line dependent. Similarly, immuno-purified hCLCA1 at physiologically relevant concentration of similar to 100 pg/mL was able to activate macrophages and induce pro-inflammatory response. This cytokine response increased with higher concentration of immuno-purified hCLCA1. These findings demonstrate the ability of hCLCA1 to function as a signaling molecule and activate macrophages, central regulators of airway inflammation.