Authors:
Fabienne T. Schulthess, Federico Paroni, Nadine S. Sauter, Luan Shu, Pascale Ribaux, Leena Haataja, Robert M. Strieter, Jose Oberholzer, Charles C. King, and Kathrin Maedler
Summary:
In type 1 and type 2 diabetes (T1/T2DM), B cell destruction by apoptosis results in decreased B cell mass and progression of the disease. In this study, we found that the interferon Y-inducible protein 10 plays an important role in triggering B 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 cells.Treatment of human islets with CXCL10 decreased B 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 B cell failure in diabetes.
Source:
Cell Metabolism; Vol. 9, Issue 2, 125-139 (02/04/09)