CXCL10 Impairs β Cell Function and Viability in Diabetes through TLR4 Signaling
CXCL10 Impairs β Cell Function and Viability in Diabetes through TLR4 Signaling
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DOI：
10.1016/j.cmet.2009.01.003
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发表时间：
2009-02-04
期刊：
影响因子：
29
通讯作者：
Maedler, Kathrin
中科院分区：
文献类型：
--
作者：
Schulthess, Fabienne T.;Paroni, Federico;Maedler, Kathrin
在1型和2型糖尿病（T1/T2 DM）中，细胞凋亡导致的β细胞破坏导致β细胞质量减少和疾病进展。在这项研究中，我们发现干扰素γ诱导蛋白10在触发β细胞破坏中起着重要作用。从T2 DM患者分离的胰岛分泌CXCL 10，其CXCL 10 mRNA含量是对照患者胰岛的33.5倍。来自肥胖非糖尿病个体和T2 DM和T1 DM患者的胰腺切片在P细胞中表达CXCL 10。用CXCL 10处理人胰岛降低β细胞活力，损害胰岛素分泌，并降低胰岛素mRNA。CXCL 10诱导Akt、JNK的持续活化和p2 l激活的蛋白激酶2（PAK-2）的裂解，将Akt信号从增殖转换为凋亡。这些作用不是由通常已知的CXCL 10受体CXCR 3介导的，而是通过TLR 4介导的。我们的数据表明CXCL 10是TLR 4的结合伴侣，也是糖尿病中0细胞衰竭的信号。
In type 1 and type 2 diabetes (T1/T2DM), beta cell destruction by apoptosis results in decreased beta cell mass and progression of the disease. In this study, we found that the interferon gamma-inducible protein 10 plays an important role in triggering beta cell destruction. Islets isolated from patients with T2DM secreted CXCL10 and contained 33.5-fold more CXCL10 mRNA than islets from control patients. Pancreatic sections from obese nondiabetic individuals and patients with T2DM and T1DM expressed CXCL10 in P cells.Treatment of human islets with CXCL10 decreased beta cell viability, impaired insulin secretion, and decreased insulin mRNA. CXCL10 induced sustained activation of Akt, JNK, and cleavage of p2l-activated protein kinase 2 (PAK-2), switching Akt signals from proliferation to apoptosis. These effects were not mediated by the commonly known CXCL10 receptor CXCR3 but through TLR4. Our data suggest CXCL10 as a binding partner for TLR4 and as a signal toward 0 cell failure in diabetes.