Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5532-5541. doi: 10.1073/pnas.1912702117. Epub 2020 Feb 20.
The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose-response, and gene-silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). In the promoters of , , and , we found a putative CUX1-NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of , encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.
基质成纤维细胞在慢性炎症中的作用正在显现。在类风湿关节炎中，白细胞衍生的细胞因子 TNF 和 IL-17A 协同作用，激活成纤维细胞成为标志性细胞因子 IL-6 的主要来源。然而，IL-17A 单独对成纤维细胞的作用很小。为了鉴定人滑膜成纤维细胞对 TNF 和 IL-17A 协同反应的关键介质，我们进行了时间序列、剂量反应和基因沉默转录组学实验。在这里，我们表明，与 TNF 联合使用时，IL-17A 选择性地诱导一组由包括 CUT 样同源盒 1 (CUX1) 和 IκBζ (NFKBIZ) 在内的因子介导的特定基因。在 、 和 的启动子中，我们发现了一个假定的 CUX1-NF-κB 结合基序，在基因组的其他地方没有发现。CUX1 和 NF-κB p65 独立于 LIFR、STAT3、STAT4 和 ELF3 介导这些基因的转录。编码非典型 IκB 因子 IκBζ 的 基因的转录是 IL-17A 剂量依赖性的，IκBζ 仅介导对 TNF 和 IL-17A 的转录反应，但不介导对 TNF 的单独反应。在成纤维细胞中，IL-17A 反应依赖于 CUX1 和 IκBζ 来结合 NF-κB 复合物，以产生趋化因子招募中性粒细胞和单核细胞。
