Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Spain.
Pharmacol Res. 2013 Apr;70(1):20-6. doi: 10.1016/j.phrs.2012.12.004. Epub 2012 Dec 28.
Chondroitin sulfate (CS) is a natural glycosaminoglycan, formed by the 1-3 linkage of d-glucuronic acid to N-acetylgalactosamine, present in the extracellular matrix. It is used as a slow acting disease modifying agent in the treatment of osteoarthritis, and part of its beneficial effects are due to its antiinflammatory properties that result from an inhibitory effect on NF-κB signaling pathway. This ability raises the hypothesis that CS might be effective in other chronic inflammatory processes such as psoriasis, in which a deregulation of NF-κB is a key feature. In addition, psoriasis is characterized by an upregulation of STAT3 signaling pathway that is related to the epidermal hyperplasia. In the present study we report the pharmacological modulation of the NF-κB and STAT3 signaling pathways by CS in normal human keratinocytes. CS inhibited NF-κB activation and the release of some of the key psoriatic cytokines such as TNFα, IL-8, IL-6 and CCL27. Moreover, it impaired STAT3 translocation to the nucleus and significantly reduced STAT3 transcriptional activity by a mechanism that was independent from STAT3 phosphorylation. Our results confirm the interest of CS as a candidate for future drug research in the therapeutics of psoriasis given the need of more effective and safer oral medications for these patients.
硫酸软骨素（CS）是一种天然的糖胺聚糖，由 D-葡萄糖醛酸通过 1-3 键与 N-乙酰半乳糖胺连接而成，存在于细胞外基质中。它被用作治疗骨关节炎的一种缓慢作用的疾病修饰药物，其部分有益作用归因于其抗炎特性，这是由于其对 NF-κB 信号通路的抑制作用。这种能力提出了这样一种假设，即 CS 可能对其他慢性炎症过程如银屑病有效，在银屑病中，NF-κB 的失调是一个关键特征。此外，银屑病的特征是 STAT3 信号通路的上调，这与表皮过度增生有关。在本研究中，我们报告了 CS 对正常人角质形成细胞中 NF-κB 和 STAT3 信号通路的药理学调节。CS 抑制 NF-κB 激活和一些关键银屑病细胞因子的释放，如 TNFα、IL-8、IL-6 和 CCL27。此外，它通过一种独立于 STAT3 磷酸化的机制损害 STAT3 向核内的易位，并显著降低 STAT3 转录活性。鉴于这些患者需要更有效和更安全的口服药物，我们的研究结果证实了 CS 作为银屑病治疗未来药物研究的候选药物的重要性。
