Lung fibroblasts play a central role in maintaining lung homeostasis and facilitating repair through the synthesis and organization of the extracellular matrix (ECM). This study investigated the cross-talk between interleukin-1 alpha (IL-1α) and transforming growth factor-β (TGF-β) signaling, two key regulators in tissue repair and fibrosis, in the context of lung fibroblast repair in the healthy lung. Stimulation of lung fibroblasts with TGF-β1 and TGF-β2 induced collagen-I and fibronectin protein expression ( < 0.05), a response inhibited with co-treatment with IL-1α ( < 0.05). Additionally, TGF-β1 and TGF-β2 induced myofibroblast differentiation, and collagen-I gel contraction, which were both suppressed by IL-1α ( < 0.05). In contrast, interleukin (IL)-6, IL-8 and thymic stromal lymphopoietin induced by IL-1α, were unaffected by TGF-β1 or TGF-β2. Mechanistically, IL-1α administration led to the suppression of TGF-β1 and TGF-β2 signaling, through downregulation of mRNA and protein for TGF-β receptor II and the downstream adaptor protein TRAF6, but not through miR-146a that is known to be induced by IL-1α. IL-1α acts as a master regulator, modulating TGF-β1 and TGF-β2-induced ECM production, remodeling, and myofibroblast differentiation in human lung fibroblasts, playing a vital role in balancing tissue repair versus fibrosis. Further research is required to understand the dysregulated cross-talk between IL-1α and TGF-β signaling in chronic lung diseases and the exploration of therapeutic opportunities. Primary human lung fibroblasts (PHLF) were treated with media control, or 1 ng/ml IL-1α with or without 50 ng/ml TGF-β1 or TGF-β2 for 1, 6 and 72 h. Cell lysates were assessed for the expression of ECM proteins and signaling molecules by western blot, miRNA by qPCR, mRNA by RNA sequencing and cell supernatants for cytokine production by ELISA. PHLFs were also seeded in non-tethered collagen-I gels to measure contraction, and myofibroblast differentiation using confocal microscopy.

中文翻译：

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Interleukin-1α 抑制转化生长因子-β1 和 β2 诱导的人肺成纤维细胞的细胞外基质产生、重塑和信号传导：肺粘膜修复的主要调节因子


肺成纤维细胞在维持肺稳态和通过细胞外基质（ECM）的合成和组织促进修复方面发挥着核心作用。本研究调查了健康肺部肺成纤维细胞修复过程中组织修复和纤维化的两个关键调节因子白介素 1 α (IL-1α) 和转化生长因子 β (TGF-β) 信号之间的交互作用。用 TGF-β1 和 TGF-β2 刺激肺成纤维细胞会诱导 I 型胶原蛋白和纤连蛋白表达 ( < 0.05)，而与 IL-1α 共同治疗会抑制这种反应 ( < 0.05)。此外，TGF-β1 和 TGF-β2 诱导肌成纤维细胞分化和 I 型胶原凝胶收缩，而这些均被 IL-1α 抑制 ( < 0.05)。相反，IL-1α诱导的白细胞介素（IL）-6、IL-8和胸腺基质淋巴细胞生成素不受TGF-β1或TGF-β2的影响。从机制上讲，IL-1α 给药通过下调 TGF-β 受体 II 的 mRNA 和蛋白以及下游接头蛋白 TRAF6 来抑制 TGF-β1 和 TGF-β2 信号传导，但不是通过已知的 miR-146a 来抑制 TGF-β1 和 TGF-β2 信号传导。由IL-1α诱导。 IL-1α 作为主调节因子，调节 TGF-β1 和 TGF-β2 诱导的人肺成纤维细胞中 ECM 的产生、重塑和肌成纤维细胞分化，在平衡组织修复与纤维化方面发挥着至关重要的作用。需要进一步的研究来了解慢性肺病中 IL-1α 和 TGF-β 信号传导之间失调的串扰并探索治疗机会。原代人肺成纤维细胞 (PHLF) 用培养基对照或 1 ng/ml IL-1α（含或不含 50 ng/ml TGF-β1 或 TGF-β2）处理 1、6 和 72 小时。 通过蛋白质印迹评估细胞裂解物中 ECM 蛋白和信号分子的表达，通过 qPCR 评估 miRNA，通过 RNA 测序评估 mRNA，并通过 ELISA 评估细胞上清液中细胞因子的产生。 PHLF 还被接种在非束缚 I 型胶原蛋白凝胶中，以使用共聚焦显微镜测量收缩和肌成纤维细胞分化。