CXCL10通过Toll样受体4信号通路损害糖尿病患者的β细胞功能及生存能力。
CXCL10 impairs beta cell function and viability in diabetes through TLR4 signaling.
作者信息
Schulthess Fabienne T, Paroni Federico, Sauter Nadine S, Shu Luan, Ribaux Pascale, Haataja Leena, Strieter Robert M, Oberholzer Jose, King Charles C, Maedler Kathrin
机构信息
Larry L. Hillblom Islet Research Center, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cell Metab. 2009 Feb;9(2):125-39. doi: 10.1016/j.cmet.2009.01.003.
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 beta 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 p21-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 beta cell failure in diabetes.
在1型和2型糖尿病（T1/T2DM）中，细胞凋亡导致的β细胞破坏会致使β细胞数量减少并促使疾病进展。在本研究中，我们发现干扰素γ诱导蛋白10在引发β细胞破坏过程中发挥着重要作用。从2型糖尿病患者分离出的胰岛分泌趋化因子配体10（CXCL10），其CXCL10信使核糖核酸（mRNA）含量比对照患者的胰岛高33.5倍。肥胖非糖尿病个体以及2型和1型糖尿病患者的胰腺切片中，β细胞表达CXCL10。用CXCL10处理人胰岛会降低β细胞活力、损害胰岛素分泌并减少胰岛素mRNA。CXCL10诱导Akt、c-Jun氨基末端激酶（JNK）持续激活以及p21激活蛋白激酶2（PAK-2）裂解，使Akt信号从增殖转变为凋亡。这些效应并非由常见的CXCL10受体CXCR3介导，而是通过Toll样受体4（TLR4）介导。我们的数据表明，CXCL10是TLR4的结合伴侣，也是糖尿病中β细胞功能衰竭的信号。
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