Nguyen Hung N, Noss Erika H, Mizoguchi Fumitaka, Huppertz Christine, Wei Kevin S, Watts Gerald F M, Brenner Michael B
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Immunity. 2017 Feb 21;46(2):220-232. doi: 10.1016/j.immuni.2017.01.004.
Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1β. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.
成纤维细胞是炎症的主要促成者和调节者，在类风湿性关节炎等炎症性疾病中是白细胞介素-6（IL-6）的主要产生者。然而，与白细胞相比，成纤维细胞中炎症信号通路的调控在很大程度上尚不清楚。在此，我们报告，对与IL-6协同上调的基因的分析表明，信号转导和转录激活因子4（STAT4）和白血病抑制因子（LIF）可能存在联系。基因沉默显示，STAT4是IL-6转录所必需的。成纤维细胞激活后，STAT4被招募到IL-6启动子区域，LIF受体（LIFR）和STAT4形成分子复合物，该复合物与JAK1和TYK2激酶一起控制STAT4的激活。重要的是，一个涉及自分泌LIF、LIFR和STAT4的正反馈回路驱动了IL-6的持续转录。除IL-6外，这个自分泌回路还驱动了包括IL-8、粒细胞集落刺激因子（G-CSF）、IL-33、IL-11、IL-1α和IL-1β在内的其他关键炎症因子的产生。这些发现表明，成纤维细胞介导的炎症的转录调控与白细胞不同。
