Institute of Respiratory Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
Mol Biol Rep. 2011 Jan;38(1):601-9. doi: 10.1007/s11033-010-0146-7. Epub 2010 Apr 3.
Human airway epithelial cells (HAEC) may contribute to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) through toll-like receptors (TLRs)-mediated molecular mechanisms. TLRs exist on the surface of HAEC where binding to their cognate ligands initiates airway inflammation. Single immunoglobulin interleukin-1 receptor-related protein (SIGIRR) is a member of the toll-interleukin-1 receptor (TIR) family that can negatively modulate the immune response. We carried out studies to characterize SIGIRR modulation of TLR-mediated immune response in HAEC and to define its mechanisms of action. Following treatment with various concentrations of LPS, flagellin and CpG DNA, the levels of cognate TLRs 4, 5, and 9 were measured in the supernatants of HAEC over-expressing the SIGIRR molecule. Moreover, the interaction of the TLR adaptor myeloid differentiation factor 88 (MyD88) with SIGIRR in response to LPS-, flagellin- and CpG DNA-stimulation was examined by co-immunoprecipitation. The findings from this study revealed that overexpression of SIGIRR in HAEC stimulated by LPS, flagellin or CpG DNA resulted in attenuated production of the inflammatory mediators IL-6 and TNF-α. This attenuation was not the result of decreased expression of TLR4, 5 or 9, but rather a sequestration of MyD88 to the TLRs. In conclusion, SIGIRR can inhibit TLR4, 5, and 9-mediated immune responses in HAEC and may be a valuable therapeutic target for the prevention of ALI/ARDS.
人呼吸道上皮细胞(HAEC)可能通过 Toll 样受体(TLR)介导的分子机制促进急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)。TLR 存在于 HAEC 的表面,与它们的同源配体结合会引发气道炎症。单免疫球蛋白白介素 1 受体相关蛋白(SIGIRR)是 Toll-白介素 1 受体(TIR)家族的一员,能够负向调节免疫反应。我们进行了研究,以表征 SIGIRR 对 HAEC 中 TLR 介导的免疫反应的调节作用,并确定其作用机制。在用不同浓度的 LPS、鞭毛蛋白和 CpG DNA 处理后,测量了过表达 SIGIRR 分子的 HAEC 上清液中同源 TLR4、5 和 9 的水平。此外,通过共免疫沉淀检查了 TLR 衔接子髓样分化因子 88(MyD88)与 LPS、鞭毛蛋白和 CpG DNA 刺激下 SIGIRR 的相互作用。这项研究的结果表明,LPS、鞭毛蛋白或 CpG DNA 刺激的 HAEC 中 SIGIRR 的过表达导致炎症介质 IL-6 和 TNF-α 的产生减少。这种衰减不是 TLR4、5 或 9 表达减少的结果,而是 MyD88 与 TLR 结合的结果。总之,SIGIRR 可以抑制 HAEC 中 TLR4、5 和 9 介导的免疫反应,可能是预防 ALI/ARDS 的有价值的治疗靶点。