The immune-regulatory compound histamine is involved in the metabolism of the essential skin component hyaluronan (HA). We previously reported that histamine up-regulates the expression of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization, also called CEMIP or KIAA1199), which plays a key role in HA degradation. However, no information is available about histamine's effects on HA synthase (HAS) expression, the molecular sizes of HA species produced, and histamine receptors and their signaling pathways in skin fibroblasts. Moreover, histamine's effects on photoaged skin remain elusive. Here, we show that histamine increases HA degradation by up-regulating HYBID and down-regulating HAS2 in human skin fibroblasts in a dose- and time-dependent manner and thereby decreases the total amounts and sizes of newly produced HA. Histamine H1 blocker abrogated the histamine effects on HYBID up-regulation, HAS2 suppression, and HA degradation. Histamine H1 agonist exhibited effects on HA levels, composition, and breakdown similar to those of histamine. Of note, blockade of protein kinase Cδ or PI3K-Akt signaling abolished histamine-mediated HYBID stimulation and HAS2 suppression, respectively. Immunohistochemical experiments revealed a significant ∼2-fold increase in tryptase-positive mast cells in photoaged skin, where HYBID and HAS2 expression levels were increased and decreased, respectively, compared with photoprotected skin. These results indicate that histamine controls HA metabolism by up-regulating HYBID and down-regulating HAS2 via distinct signaling pathways downstream of histamine receptor H1. They further suggest that histamine may contribute to photoaged skin damage by skewing HA metabolism toward degradation.

中文翻译：

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HYBID（别名KIAA1199 / CEMIP）和透明质酸合酶可协同调节组胺刺激的皮肤成纤维细胞中的透明质酸代谢。

免疫调节化合物组胺参与必需的皮肤成分透明质酸（HA）的代谢。我们先前曾报道，组胺上调HYBID（参与透明质酸解聚的透明质酸结合蛋白，也称为CEMIP或KIAA1199）的表达，其在HA降解中起关键作用。但是，尚无有关组胺对HA合酶（HAS）表达的影响，产生的HA种类的分子大小以及皮肤成纤维细胞中组胺受体及其信号传导途径的信息。此外，组胺对光老化皮肤的影响仍然难以捉摸。在这里，我们表明，组胺通过上调HYBID和下调人皮肤成纤维细胞中的HAS2以剂量和时间依赖的方式增加HA的降解，从而减少了新产生的HA的总量和大小。组胺H1阻滞剂废除了组胺对HYBID上调，HAS2抑制和HA降解的影响。组胺H1激动剂对HA水平，组成和分解的影响与组胺相似。值得注意的是，蛋白激酶Cδ或PI3K-Akt信号传导的阻滞分别消除了组胺介导的HYBID刺激和HAS2抑制。免疫组织化学实验表明，光老化皮肤中类胰蛋白酶阳性肥大细胞显着增加约2倍，与光保护皮肤相比，HYBID和HAS2表达水平分别升高和降低。这些结果表明，组胺通过上调HYBID并通过组胺受体H1下游不同的信号通路下调HAS2来控制HA代谢。