Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron, Chicago, IL 60611, USA.
Am J Respir Cell Mol Biol. 2011 Jul;45(1):145-53. doi: 10.1165/rcmb.2010-0075OC. Epub 2010 Sep 24.
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-1β, 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-κB 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.
白细胞介素-1 家族细胞因子，现在包括 11 个成员，众所周知参与炎症反应。尽管最近被识别的白细胞介素-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调节尚未得到广泛研究。我们研究了原代正常人类支气管上皮细胞中 IL-1F5-11 的调节。TNF、IL-1β、IL-17 和 Toll 样受体（TLR）3 配体双链（ds）RNA 显著上调了 IL-1F6 和 IL-1F9 的信使（m）RNA，但不上调 IL-1F5、IL-1F8 或 IL-1F10。一些测试的细胞因子轻度上调了 IL-1F7 和 IL-1F11（IL-33）的 mRNAs。值得注意的是，TNF/IL-17 或 dsRNA/IL-17 的联合增强了 IL-1F6 和 IL-1F9 的 mRNAs 的协同增强。刺激 dsRNA 或 dsRNA 和 IL-17 的组合后，可在细胞上清液中检测到 IL-1F9 蛋白。在细胞裂解物中检测到 IL-1F6 蛋白，但在细胞上清液中未检测到。我们筛选了 IL-1F9 的受体，并发现肺成纤维细胞表达该受体。我们发现 IL-1F9 激活了原代正常人类肺成纤维细胞中的丝裂原激活蛋白激酶和转录因子 NF-κB。IL-1F9 还刺激了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（例如，通过呼吸道病毒感染）的上皮细胞激活以及 Th17 细胞（IL-17）和炎症细胞（TNF）产生的细胞因子的暴露，可能通过诱导 IL-1F9 和激活成纤维细胞来放大气道中的中性粒细胞炎症。
