CXCL10 Impairs β Cell Function and Viability in Diabetes through TLR4 Signaling

被引：184

作者：

Schulthess, Fabienne T. ^{[1
,2
]}

Paroni, Federico ^{[2
]}

Sauter, Nadine S. ^{[1
]}

Shu, Luan ^{[1
,2
]}

Ribaux, Pascale ^{[3
]}

Haataja, Leena ^{[1
]}

Strieter, Robert M. ^{[4
]}

Oberholzer, Jose ^{[5
]}

King, Charles C. ^{[6
]}

Maedler, Kathrin ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, Dept Med, Larry L Hillblom Islet Res Ctr, Los Angeles, CA 90095 USA

[2] Univ Bremen, Ctr Biomol Interact, D-28359 Bremen, Germany

[3] Univ Med Ctr, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[4] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA

[5] Univ Illinois, Div Transplantat, Chicago, IL 60612 USA

[6] Univ Calif San Diego, Ctr Mol Genet, Dept Pediat, La Jolla, CA 92093 USA

来源：

CELL METABOLISM | 2009年 / 9卷 / 02期

关键词：

INTERFERON-INDUCIBLE PROTEIN-10; IFN-GAMMA; PHOSPHATIDYLINOSITOL; 3-KINASE/AKT; CHEMOKINE IP-10/CXCL10; INSULIN-RESISTANCE; PANCREATIC-ISLETS; INNATE IMMUNITY; CUTTING EDGE; FATTY-ACIDS; EXPRESSION;

D O I：

10.1016/j.cmet.2009.01.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：125 / 139

页数：15

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