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Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):86-97. doi: 10.1016/j.bbadis.2018.09.030. Epub 2018 Oct 1.

TLR4 triggered complex inflammation in human pancreatic islets.

Author information

1
University of Bremen, Center for Biomolecular Interactions Bremen, Germany. Electronic address: hewei@uni-bremen.de.
2
University of Bremen, Center for Biomolecular Interactions Bremen, Germany.
3
Department of Health Sciences, Magna Graecia University, Catanzaro, Italy.
4
ADIR - Groupe de Recherche Servier, Suresnes, France.
5
University of Bremen, Center for Biomolecular Interactions Bremen, Germany. Electronic address: kmaedler@uni-bremen.de.

Abstract

Type 2 Diabetes (T2D) is strongly associated with obesity and inflammation. Toll-like receptor-4 (TLR-4) is the major pro-inflammatory pathway with its ligands and downstream products increased systemically in T2D and in at-risk individuals. Detailed mechanisms of the complex proinflammatory response in pancreatic islets remain unknown. In isolated human islets LPS induced IL-1β, IL-6, IL-8 and TNF production in a TLR4-dependent manner and severely impaired β-cell survival and function. IL-6 antagonism improved β-cell function. IL-8, which was identified specifically in α-cells, initiated monocyte migration, a process fully blocked by IL-8 neutralization. The TLR4 response was potentiated in obese donors; with higher IL-1β, IL-6 and IL-8 expression than in non-obese donors. TLR4 activation leads to a complex multi-cellular inflammatory response in human islets, which involves β-cell failure, cytokine production and macrophage recruitment to islets. In obesity, the amplified TLR4 response may potentiate β-cell damage and accelerate diabetes progression.

KEYWORDS:

Apoptosis; Chemokine; Cytokine; Inflammation; Insulin; Obesity; TLR4; Type 2 diabetes; α-Cells; β-Cells

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