Zhang L W, Cong X, Zhang Y, Wei T, Su Y C, Serrão A C A, Brito A R T, Yu G Y, Hua H, Wu L L
Department of Oral Medicine and Center for Salivary Gland Diseases of Peking University School and Hospital of Stomatology, Beijing, P.R. China.
Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China.
J Dent Res. 2016 Jul;95(7):784-92. doi: 10.1177/0022034516634647. Epub 2016 Mar 1.
Sjögren's syndrome (SS) is an inflammatory autoimmune disease that causes secretory dysfunction of the salivary glands. It has been reported that proinflammatory cytokine interleukin-17 (IL-17) was elevated and tight junction (TJ) integrity disrupted in minor salivary glands from SS patients. However, whether the elevated IL-17 in SS affects TJ integrity and thereby alters the function of salivary gland is unknown. Here, by using nonobese diabetic (NOD) mice as SS model, we found that the stimulated salivary flow rate was significantly decreased in NOD mice. Lymphocyte infiltration was mainly observed in submandibular glands (SMGs), but not parotid glands (PGs), of NOD mice. IL-17 was significantly increased and mainly located in lymphocytic-infiltrating regions in SMGs but not detectable in PGs of NOD mice. Meanwhile, the epithelial barrier function was disrupted, as evidenced by an increased paracellular tracer clearance and an enlarged acinar TJ width in SMGs of NOD mice. Furthermore, claudin-1 and -3 were elevated especially at the basolateral membranes, whereas claudin-4, occludin, and zonula occludens-1 (ZO-1) were reduced in SMGs of NOD mice. Moreover, occludin and ZO-1 were dispersed into cytoplasm in SMGs of NOD mice. However, no change in the expression and distribution of TJ proteins was found in PGs. In vitro, IL-17 significantly decreased the levels and apical staining of claudin-4 and ZO-1 proteins in the cultured SMG tissues, as well as claudin-1, occludin, and ZO-1 in PG tissues. Moreover, IL-17 activated the phosphorylation of IκBα and p65 in SMG cells, whereas pretreatment with NF-κB inhibitor pyrrolidine dithiocarbamate suppressed the IL-17-induced downregulation of claudin-4 and ZO-1 in SMG tissues. Taken together, these findings indicate that IL-17 derived from infiltrating lymphocyte impairs the integrity of TJ barrier through NF-κB signaling pathway, and thus might contribute to salivary gland dysfunction in SS.
干燥综合征（SS）是一种炎症性自身免疫性疾病，可导致唾液腺分泌功能障碍。据报道，促炎细胞因子白细胞介素-17（IL-17）升高，且SS患者小唾液腺中的紧密连接（TJ）完整性遭到破坏。然而，SS中升高的IL-17是否会影响TJ完整性，进而改变唾液腺功能尚不清楚。在此，我们以非肥胖糖尿病（NOD）小鼠作为SS模型，发现NOD小鼠的刺激唾液流速显著降低。主要在NOD小鼠的下颌下腺（SMG）而非腮腺（PG）中观察到淋巴细胞浸润。IL-17显著增加，主要位于NOD小鼠SMG的淋巴细胞浸润区域，而在PG中未检测到。同时，上皮屏障功能遭到破坏，NOD小鼠SMG中细胞旁示踪剂清除增加和腺泡TJ宽度增大证明了这一点。此外，claudin-1和-3升高，尤其是在基底外侧膜处，而claudin-4、闭合蛋白和紧密连接蛋白-1（ZO-1）在NOD小鼠的SMG中减少。此外，闭合蛋白和ZO-1在NOD小鼠的SMG中分散到细胞质中。然而，在PG中未发现TJ蛋白的表达和分布有变化。在体外，IL-17显著降低了培养的SMG组织中claudin-4和ZO-1蛋白的水平及顶端染色，以及PG组织中claudin-1、闭合蛋白和ZO-1的水平及顶端染色。此外，IL-17激活了SMG细胞中IκBα和p65的磷酸化，而用NF-κB抑制剂吡咯烷二硫代氨基甲酸盐预处理可抑制IL-17诱导的SMG组织中claudin-4和ZO-1的下调。综上所述这些发现表明，浸润淋巴细胞产生的IL-17通过NF-κB信号通路损害TJ屏障的完整性，因此可能导致SS中的唾液腺功能障碍。
