TSLP-induced collagen type-I synthesis through STAT3 and PRMT1 is sensitive to calcitriol in human lung fibroblasts
TSLP-induced collagen type-I synthesis through STAT3 and PRMT1 is sensitive to calcitriol in human lung fibroblasts
复制标题
TSLP 通过 STAT3 和 PRMT1 诱导的 I 型胶原合成对人肺成纤维细胞中的骨化三醇敏感。
DOI：
10.1016/j.bbamcr.2021.119083
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发表时间：
2021-06-28
影响因子：
5.1
通讯作者：
Lu, Shemin
中科院分区：
文献类型：
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作者：
Jin, Ai;Tang, Xuemei;Lu, Shemin
哮喘的主要病理机制之一是气道壁重构，它与维生素D缺乏和上皮下层蛋白精氨酸甲基转移酶-1(PRMT1)的表达有关。骨化三醇可减轻哮喘模型的重塑，但其作用机制尚不清楚。这项研究评估了骨化三醇对人肺成纤维细胞PRMT1依赖的成纤维细胞重塑和E3-大鼠变应原诱导的哮喘的影响。用胸腺基质淋巴生成素(TLSP)激活成纤维细胞；用卵清蛋白吸入诱导大鼠哮喘。采用免疫组织化学方法评价大鼠的气道结构。Western-blotting检测成纤维细胞蛋白表达及丝裂原活化蛋白激酶活性。用荧光素酶报告试剂盒检测转录因子的激活。PRMT1的作用被siRNA和PRMT-抑制所阻断。卵清蛋白上调上皮下成纤维细胞TSLP、PRMT1、基质金属蛋白酶-1(MMP1)、白介素25和I型胶原的表达。在分离的成纤维细胞中，TSLP诱导同样的蛋白，这些蛋白被ERK1/2和p38抑制而被阻断。TLSP通过激活信号转导和转录激活因子-3诱导PRMT1的表达。抑制PRMT1可减少I型胶原的表达，并抑制MMP1。在成纤维细胞中，补充骨化三醇超过12天可通过阻断PRMT1水平来阻止TSLP诱导的重塑。有趣的是，短期的骨化三醇治疗没有这样的效果。这些数据支持骨化三醇在哮喘治疗中的有益作用。
Airway wall remodeling, a main pathology of asthma was linked to vitamin-D deficiency and protein arginine methyltransferase-1 (PRMT1) expression in sub-epithelial cell layers. Calcitriol reduced remodeling in asthma model, but its mode of action is unclear. This study assessed the effect of calcitriol on PRMT1-dependent fibroblast remodeling in human lung fibroblasts, and allergen-induced asthma in E3-rats. Fibroblasts were activated with thymic stromal lymphopoietin (TLSP); asthma was induced by ovalbumin inhalation in rats. The airway structure was assessed by immunohistology. Protein expression in fibroblasts and activation of the mitogen activated protein kinases were detected by Western-blotting. Transcription factor activation was determined by luciferase reporter assay. PRMT1 action was blocked by siRNA and PRMT-inhibition. Ovalbumin upregulated the expression of TSLP, PRMT1, matrix metallopro-teinase-1 (MMP1), interleukin-25, and collagen type-I in sub-epithelial fibroblasts. In isolated fibroblasts, TSLP induced the same proteins, which were blocked by inhibition of Erk1/2 and p38. TLSP induced PRMT1 through activation of signal transducer and activator of transcription-3. PRMT1 inhibition reduced collagen type-I expression and suppressed MMP1. In fibroblasts, calcitriol supplementation over 12 days prevented TSLP-induced remodeling by blocking the PRMT1 levels. Interestingly, short-term calcitriol treatment had no such effect. The data support the beneficial role of calcitriol in asthma therapy.