Department of Rheumatology, Radboud University Nijmegen Medical Centre, the Netherlands.
Scand J Rheumatol. 2009;38(4):282-90. doi: 10.1080/03009740802572467.
It has been suggested that the T-cell attracting and profibrotic chemokine CCL18 might play a role in the pathogenesis of systemic sclerosis (SSc). However, it is unclear what underlies the higher CCL18 levels in SSc. The aim of our study was to determine whether Toll-like receptor (TLR)-mediated stimulation of monocytes and dendritic cells (DCs) contributes to the higher levels of CCL18 in SSc.
CCL18 levels were measured in 40 patients with SSc, primary Raynaud's phenomenon (RP) and healthy controls. The presence of TLR4 agonists in the circulation of SSc patients was investigated using TLR4 transgenic Chinese hamster ovary (CHO) cells. CCL18 and interleukin (IL)-10 secretion by monocytes/macrophages and monocyte-derived DCs (moDCs) was measured in the supernatant. The indirect effect of lipopolysaccharide (LPS)-stimulated moDCs on CCL18 secretion by monocytes/macrophages was investigated using a transwell system.
CCL18 levels were significantly elevated in SSc patients compared to patients with RP and healthy controls. SSc sera strongly induced CD25 expression on CHO cells genetically modified to express TLR4 but not on those expressing CD14 only. By contrast, serum from systemic lupus erythematosus (SLE) patients or healthy individuals did not have an effect. Neither monocytes/macrophages nor moDCs from SSc patients secreted higher levels of CCL18 compared to healthy controls. However, moDCs matured with the TLR4 ligand LPS from patients with SSc did secrete significantly higher amounts of IL-10 compared to those from healthy counterparts, which were IL-10 dependent.
Our results suggest that elevated CCL18 levels in SSc are not caused by an intrinsically enhanced CCL18 secretion by monocytes/macrophages but are, at least partly, orchestrated by an enhanced IL-10 secretion by TLR4-stimulated DCs. These observations suggest a role for TLR4 ligands and DCs in the pathogenesis of SSc, a topic that warrants further investigation.
趋化因子 CCL18 具有吸引 T 细胞和促进纤维化的作用，可能在系统性硬化症（SSc）的发病机制中发挥作用。然而，导致 SSc 患者 CCL18 水平升高的原因尚不清楚。本研究旨在确定 Toll 样受体（TLR）介导的单核细胞和树突状细胞（DC）刺激是否导致 SSc 患者 CCL18 水平升高。
检测了 40 例 SSc 患者、原发性雷诺现象（RP）患者和健康对照者的 CCL18 水平。采用 TLR4 转基因中国仓鼠卵巢（CHO）细胞检测 SSc 患者循环中 TLR4 激动剂的存在。测量单核细胞/巨噬细胞和单核细胞来源的 DC（moDC）上清液中 CCL18 和白细胞介素（IL）-10 的分泌。通过 Transwell 系统研究 LPS 刺激的 moDC 对单核细胞/巨噬细胞分泌 CCL18 的间接影响。
与 RP 患者和健康对照组相比，SSc 患者的 CCL18 水平显著升高。与仅表达 CD14 的 CHO 细胞相比，经基因修饰表达 TLR4 的 CHO 细胞强烈诱导 SSc 血清中 CD25 的表达，但来自系统性红斑狼疮（SLE）患者或健康个体的血清则无此作用。与健康对照组相比，SSc 患者的单核细胞/巨噬细胞或 moDC 并未分泌更高水平的 CCL18。然而，与健康对照组相比，来自 SSc 患者的经 TLR4 配体 LPS 成熟的 moDC 确实分泌了显著更高水平的 IL-10，这是 IL-10 依赖性的。
我们的结果表明，SSc 患者 CCL18 水平升高不是由单核细胞/巨噬细胞固有地增强 CCL18 分泌引起的，而是至少部分由 TLR4 刺激的 DC 增强的 IL-10 分泌所协调。这些观察结果表明 TLR4 配体和 DC 在 SSc 的发病机制中起作用，这是一个值得进一步研究的课题。
