Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
Sci Rep. 2016 Sep 21;6:34012. doi: 10.1038/srep34012.
Raynaud's phenomenon is frequently observed in systemic sclerosis (SSc) patients, and cold- or stress-induced norepinephrine (NE) has been speculated to be associated with vasoconstriction. Objective was to elucidate the role of NE in fibrosis in SSc. IL-6 is a potent stimulator of collagen production in fibroblasts. NE enhanced IL-6 production and proliferation more significantly in SSc fibroblasts than in normal fibroblasts. Furthermore, the production of IL-6 and phosphorylation of p38 in SSc fibroblasts was enhanced by adrenergic receptor (AR)β agonist, isoproterenol, but not ARα agonist, oxymetazoline. ARβ blocker, propranolol, inhibited NE-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. NE-induced IL-6 was significantly inhibited by p38 inhibitor, SB203580, suggesting that NE-induced phosphorylation of p38 via ARβ enhances IL-6 production in SSc fibroblasts. NE-induced phosphorylation of ERK1/2 via ARα inhibited IL-6 production in SSc fibroblasts. Combined treatment with NE and endothelin-1 resulted in an additive increase in IL-6 production in SSc fibroblasts. NE-induced IL-6/IL-6 receptor trans-signaling increased the production of collagen type I in SSc fibroblasts, and both propranolol and SB203580 inhibited NE-induced collagen production. These results suggest that cold exposure and/or emotional stress-induced NE might contribute to the skin fibrosis via potentiation of IL-6 production from fibroblasts in SSc.
雷诺现象在系统性硬化症（SSc）患者中经常观察到，冷或应激诱导的去甲肾上腺素（NE）被推测与血管收缩有关。目的是阐明 NE 在 SSc 纤维化中的作用。IL-6 是成纤维细胞胶原产生的有力刺激物。NE 增强 SSc 成纤维细胞中 IL-6 的产生和增殖作用明显大于正常成纤维细胞。此外，SSc 成纤维细胞中 IL-6 的产生和 p38 的磷酸化作用通过肾上腺素能受体（AR）β激动剂异丙肾上腺素增强，但不是 ARα激动剂羟甲唑啉。ARβ 阻滞剂普萘洛尔抑制 SSc 成纤维细胞中 NE 诱导的 IL-6 产生和 p38 的磷酸化。NE 诱导的 IL-6 被 p38 抑制剂 SB203580 显著抑制，表明 NE 通过 ARβ 诱导的 p38 磷酸化增强 SSc 成纤维细胞中 IL-6 的产生。NE 诱导的 ERK1/2 通过 ARα 磷酸化抑制 SSc 成纤维细胞中 IL-6 的产生。NE 和内皮素-1 的联合处理导致 SSc 成纤维细胞中 IL-6 的产生增加。NE 诱导的 IL-6/IL-6 受体转信号增加 SSc 成纤维细胞中 I 型胶原的产生，普萘洛尔和 SB203580 均抑制 NE 诱导的胶原产生。这些结果表明，冷暴露和/或情绪应激诱导的 NE 可能通过增强 SSc 成纤维细胞中 IL-6 的产生，导致皮肤纤维化。
