Regulation and Function of the IL-1 Family Cytokine IL-1F9 in Human Bronchial Epithelial Cells
Regulation and Function of the IL-1 Family Cytokine IL-1F9 in Human Bronchial Epithelial Cells
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DOI：
10.1165/rcmb.2010-0075oc
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发表时间：
2011-07-01
影响因子：
6.4
通讯作者：
Kato, Atsushi
中科院分区：
文献类型：
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作者：
Chustz, Regina T.;Nagarkar, Deepti R.;Kato, Atsushi
众所周知，IL-1 细胞因子家族目前包括 11 个成员，与炎症有关。尽管最近公认的IL-1家族细胞因子（IL-1F5-11）已被证明在气道上皮细胞中表达，但它们在上皮细胞中的表达和功能的调节尚未得到广泛研究。我们研究了原代正常人支气管上皮细胞中 IL-1F5-11 的调节。 IL-1F6 和 IL-1F9 的信使 (m) RNA，但不包括 IL-1F5、IL-1F8 或 IL-1F10，被 TNF、IL-1β、IL-17 和 Toll 样受体 (TLR)3 配体双链 (ds) RNA 显着上调。 IL-1F7 和 IL-1F11 (IL-33) 的 mRNA 被一些测试的细胞因子微弱上调。值得注意的是，IL-1F6 和 IL-1F9 的 mRNA 通过 TNF/IL-17 或 dsRNA/IL-17 的组合而协同增强。用 dsRNA 或 dsRNA 与 IL-17 的组合刺激后，在上清液中检测到 IL-1F9 蛋白。在细胞裂解液中检测到 IL-1F6 蛋白，但在上清液中未检测到。我们筛选了IL-1F9的受体，发现肺成纤维细胞表达这种受体。我们发现IL-1F9在原代正常人肺成纤维细胞中激活丝裂原激活蛋白激酶和转录因子NF-κB。 IL-1F9 还刺激肺成纤维细胞中中性粒细胞趋化因子 IL-8 和 CXCL3 以及 Th17 趋化因子 CCL20 的表达。这些结果表明，TLR3 激活上皮细胞（例如，呼吸道病毒感染）以及暴露于来自 Th17 细胞 (IL-17) 和炎症细胞 (TNF) 的细胞因子可能会通过诱导 IL-1F9 和激活成纤维细胞来放大气道中的中性粒细胞炎症。
The IL-1 family of cytokines, which now includes 11 members, is well known to participate in inflammation. Although the most recently recognized IL-1 family cytokines (IL-1F5-11) have been shown to be expressed in airway epithelial cells, the regulation of their expression and function in the epithelium has not been extensively studied. We investigated the regulation of IL-1F5-11 in primary normal human bronchial epithelial cells. Messenger (m) RNAs for IL-1F6 and IL-1F9, but not IL-1F5, IL-1F8 or IL-1F10, were significantly up-regulated by TNF, IL-1 beta, IL-17 and the Toll-like receptor (TLR)3 ligand double-stranded (ds) RNA. mRNAs for IL-1F7 and IL-1F11 (IL-33) were weakly up-regulated by some of the cytokines tested. Notably, mRNAs for IL-1F6 and IL-1F9 were synergistically enhanced by the combination of TNF/IL-17 or dsRNA/IL-17. IL-1F9 protein was detected in the supernatant following stimulation with dsRNA or a combination of dsRNA and IL-17. IL-1F6 protein was detected in the cell lysate but was not detected in the supernatant. We screened for the receptor for IL-1F9 and found that lung fibroblasts expressed this receptor. We found that IL-1F9 activated mitogen-activated protein kinases and the transcription factor NF-kappa B in primary normal human lung fibroblasts. IL-1F9 also stimulated the expression of the neutrophil chemokines IL-8 and CXCL3 and the Th17 chemokine CCL20 in lung fibroblasts. These results suggest that epithelial activation by TLR3 (e. g., by respiratory viral infection) and exposure to cytokines from Th17 cells (IL-17) and inflammatory cells (TNF) may amplify neutrophilic inflammation in the airway via induction of IL-1F9 and activation of fibroblasts.