通过G蛋白调控AGS3蛋白基肽的气道炎症的调控
2016/08/31
摘要
呼吸系统疾病，如哮喘，慢性阻塞性肺疾病（COPD）和肺部感染对人类的死亡率和发病率有重要的影响。本研究的目的是探讨CXCL12影响 MUC1转录和气道炎症的机制，这取决于G蛋白信号转导（AGS）激活子3和确定通过作用于G蛋白偶联受体来抑制CXCL12诱导的气道炎症的特异性分子。本文发现，AGS3通过调节Gαi抑制CXCL12介导的MUC1和TNFα上调。我们发现G蛋白调节（GPR）AGS3基序肽结合到Gαi 并下调MUC1的表达；相反，这个基序上调TNFα的表达。突变之后的GPR Q34A 肽可增加MUC1和 TGFβ的表达但降低TNFα和IL-6的表达。此外，与GPR野生型蛋白相比，CXCR4诱导的树突状扩展的二维和三维矩阵生长能被GPR Q34A蛋白抑制。GPR Q34A蛋白也能抑制小鼠肺中CXCL12诱导的形态学改变和炎性细胞浸润，并且能够抑制支气管肺泡灌洗（BAL）液和肺中产生炎性细胞因子。我们的数据表明，AGS3的GPR基序对调节MUC1/Muc1的表达和炎性微环境中细胞因子的产生至关重要。
（杨冬 审校）
Sci Rep. 2016 Jun 7;6:27054. doi: 10.1038/srep27054.
Regulation of Airway Inflammation by G-protein Regulatory Motif Peptides of AGS3 protein.
Choi IW1, Ahn do W2, Choi JK2, Cha HJ3,4, Ock MS3, You E5, Rhee S5, Kim KC6, Choi YH7, Song KS2,4.
Author information
Abstract
Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and lung infections have critical consequences on mortality and morbidity in humans. The aims of the present study were to examine the mechanisms by which CXCL12 affects MUC1 transcription and airway inflammation, which depend on activator of G-protein signaling (AGS) 3 and to identify specific molecules that suppress CXCL12-induced airway inflammation by acting on G-protein-coupled receptors. Herein, AGS3 suppresses CXCL12-mediated upregulation of MUC1 and TNFα by regulating Gαi. We found that the G-protein regulatory (GPR) motif peptide in AGS3 binds to Gαi and downregulates MUC1 expression; in contrast, this motif upregulates TNFα expression. Mutated GPR Q34A peptide increased the expression of MUC1 and TGFβ but decreased the expression of TNFα and IL-6. Moreover, CXCR4-induced dendritic extensions in 2D and 3D matrix cultures were inhibited by the GPR Q34A peptide compared with a wild-type GPR peptide. The GPR Q34A peptide also inhibited CXCL12-induced morphological changes and inflammatory cell infiltration in the mouse lung, and production of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid and the lungs. Our data indicate that the GPR motif of AGS3 is critical for regulating MUC1/Muc1 expression and cytokine production in the inflammatory microenvironment.
Sci Rep. 2016 Jun 7;6:27054. doi: 10.1038/srep27054.
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低分子量药物比高分子量药物会导致更严重的哮喘吗？
