Department of Biochemical, Physiological and Nutritional Sciences, Section of Medical Chemistry, School of Medicine, University of Messina, Policlinico Universitario, Messina, Italy.
Arch Biochem Biophys. 2012 Feb 1;518(1):42-52. doi: 10.1016/j.abb.2011.12.005. Epub 2011 Dec 14.
Hyaluronan (HA) fragments are able to induce inflammation by stimulating both CD44 and toll-like receptor 4 (TLR-4). CD44 and TLR-4 activation stimulates the liberation of NF-kB and pro-inflammatory cytokine responses. The aim of this study was to investigate the effects of hyaluronidase (HYAL) treatment, which depolymerises HA into small fragments, and of the addition of specific hyaluronan synthases-1, 2, and 3 small interference RNA (HASs siRNA), which silence HASs activity, on normal mouse synovial fibroblasts (NSF) and on rheumatoid arthritis synovial fibroblasts (RASF) obtained from mice subjected to collagen induced arthritis (CIA). The addition of HYAL to NSF and/or RASF significantly increased the TLR-4, CD44 and NF-kB activity, as well as the pro-inflammatory cytokines, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-33 (IL-33) in both groups, but to a greater extent in RASF. The addition to NSF and/or RASF of the HASs siRNA, which block HASs activity and therefore the availability of HA substrate for HYAL, was able to reduce HYAL effects in both NSF and RASF. Finally, the HA evaluation confirmed the increment of HA at low molecular weight after HYAL treatment.
透明质酸（HA）片段能够通过刺激 CD44 和 Toll 样受体 4（TLR-4）来诱导炎症。CD44 和 TLR-4 的激活刺激 NF-kB 的释放和促炎细胞因子反应。本研究旨在探讨透明质酸酶（HYAL）处理的影响，HYAL 将 HA 解聚成小片段，以及添加特定的透明质酸合酶-1、2 和 3 小干扰 RNA（HASs siRNA），沉默 HASs 活性，对正常小鼠滑膜成纤维细胞（NSF）和胶原诱导关节炎（CIA）小鼠来源的类风湿关节炎滑膜成纤维细胞（RASF）的影响。HYAL 分别添加到 NSF 和/或 RASF 中，显著增加了 TLR-4、CD44 和 NF-kB 的活性，以及促炎细胞因子白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-33（IL-33）在两组中的表达，但在 RASF 中更为明显。添加到 NSF 和/或 RASF 的 HASs siRNA 可以阻断 HASs 活性，从而减少 HYAL 对 NSF 和 RASF 的作用。最后，HA 的评估证实了 HYAL 处理后低分子量 HA 的增加。
