Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
Am J Physiol Lung Cell Mol Physiol. 2020 Jul 1;319(1):L185-L195. doi: 10.1152/ajplung.00347.2019. Epub 2020 May 20.
S100A4 is a low-molecular-mass (12 kDa) EF-hand Ca-binding S100 protein that is expressed in a broad range of normal tissue and cell types. S100A4 can be secreted from some cells to act in an autocrine or paracrine fashion on target cells and tissues. S100A4 has been reported in the extracellular fluids of subjects with several inflammatory diseases, including asthma. Airway smooth muscle plays a critical role in airway inflammation by synthesizing and secreting inflammatory cytokines. We hypothesized that S100A4 may play an immunomodulatory role in airway smooth muscle. Trachealis smooth muscle tissues were stimulated with recombinant His-S100A4, and the effects on inflammatory responses were evaluated. S100A4 induced the activation of Akt and NF-κB and stimulated eotaxin secretion. It also increased the expression of RAGE and endogenous S100A4 in airway tissues. Stimulation of airway smooth muscle tissues with IL-13 or TNF-α induced the secretion of S100A4 from the tissues and promoted the expression of endogenous receptors for advanced glycation end products (RAGE) and S100A4. The role of RAGE in mediating the responses to S100A4A was evaluated by expressing a mutant nonfunctional RAGE (RAGEΔcyto) in tracheal muscle tissues and by treating tissues with a RAGE inhibitor. S100A4 did not activate NF-κB or Akt in tissues that were expressing RAGEΔcyto or treated with a RAGE inhibitor, indicating that S100A4 mediates its effects by acting on RAGE. Our results demonstrate that inflammatory mediators stimulate the synthesis and secretion of S100A4 in airway smooth muscle tissues and that extracellular S100A4 acts via RAGE to mediate airway smooth muscle inflammation.
S100A4 是一种低分子量（12 kDa）EF 手型 Ca 结合 S100 蛋白，在广泛的正常组织和细胞类型中表达。S100A4 可以从一些细胞中分泌出来，以自分泌或旁分泌的方式作用于靶细胞和组织。S100A4 已在几种炎症性疾病（包括哮喘）患者的细胞外液中被报道。气道平滑肌通过合成和分泌炎症细胞因子在气道炎症中发挥关键作用。我们假设 S100A4 可能在气道平滑肌中发挥免疫调节作用。用重组 His-S100A4 刺激气管平滑肌组织，并评估其对炎症反应的影响。S100A4 诱导 Akt 和 NF-κB 的激活，并刺激嗜酸性粒细胞趋化因子的分泌。它还增加了气道组织中 RAGE 和内源性 S100A4 的表达。用 IL-13 或 TNF-α 刺激气道平滑肌组织会诱导组织分泌 S100A4，并促进内源性晚期糖基化终产物受体（RAGE）和 S100A4 的表达。通过在气管肌肉组织中表达突变的无功能 RAGE（RAGEΔcyto）和用 RAGE 抑制剂处理组织，评估 RAGE 在介导对 S100A4 的反应中的作用。S100A4 不会在表达 RAGEΔcyto 的组织或用 RAGE 抑制剂处理的组织中激活 NF-κB 或 Akt，表明 S100A4 通过作用于 RAGE 来介导其作用。我们的结果表明，炎症介质刺激气道平滑肌组织中 S100A4 的合成和分泌，细胞外 S100A4 通过 RAGE 作用来介导气道平滑肌炎症。
