Yang Lingli, Murota Hiroyuki, Serada Satoshi, Fujimoto Minoru, Kudo Akira, Naka Tetsuji, Katayama Ichiro
Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan.
J Invest Dermatol. 2014 Aug;134(8):2105-2113. doi: 10.1038/jid.2014.120. Epub 2014 Feb 27.
Histamine is thought to have a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases. Recent studies revealed that periostin, a matricelluar protein, contributed to tissue remodeling; however, a link between periostin and histamine remains unproven. We investigated whether periostin was involved in histamine-induced collagen production. Cultured dermal fibroblasts derived from wild-type (WT) or periostin knockout (PN(-/-)) mice were stimulated with histamine, and then collagen and periostin production was evaluated. Histamine induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase, whereas no effect on collagen expression was observed in histamine-stimulated PN(-/-) fibroblasts. In WT fibroblasts, histamine directly induced periostin expression in a dose-dependent manner, and an H1 receptor antagonist blocked both periostin and collagen expression. Histamine activated extracellular signal-regulated kinase 1/2 (ERK1/2) through the H1 receptor. Periostin induction was inhibited by either H1 antagonist or ERK1/2 inhibitor treatment in vitro and was attenuated in H1R(-/-) mice. Elevated expression of periostin was found in lesional skin from atopic dermatitis patients. These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor-mediated ERK1/2 pathway; furthermore, histamine may accelerate the chronicity of atopic dermatitis.
组胺被认为在皮肤细胞外基质的合成中起关键作用，并且可能参与过敏性疾病的组织重塑。最近的研究表明，骨膜蛋白（一种基质细胞蛋白）有助于组织重塑；然而，骨膜蛋白与组胺之间的联系尚未得到证实。我们研究了骨膜蛋白是否参与组胺诱导的胶原蛋白生成。用组胺刺激源自野生型（WT）或骨膜蛋白基因敲除（PN(-/-)）小鼠的培养真皮成纤维细胞，然后评估胶原蛋白和骨膜蛋白的生成。组胺在晚期诱导WT成纤维细胞中的胶原蛋白基因表达，但在早期没有，而在组胺刺激的PN(-/-)成纤维细胞中未观察到对胶原蛋白表达的影响。在WT成纤维细胞中，组胺以剂量依赖性方式直接诱导骨膜蛋白表达，并且H1受体拮抗剂阻断骨膜蛋白和胶原蛋白表达。组胺通过H1受体激活细胞外信号调节激酶1/2（ERK1/2）。在体外，H1拮抗剂或ERK1/2抑制剂处理可抑制骨膜蛋白的诱导，并且在H1R(-/-)小鼠中减弱。在特应性皮炎患者的皮损中发现骨膜蛋白表达升高。这些结果表明，组胺通过激活H1受体介导的ERK1/2途径介导骨膜蛋白诱导和胶原蛋白生成；此外，组胺可能会加速特应性皮炎的慢性化。
