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Free Fatty Acids Induce a Proinflammatory Response in Islets via the Abundantly Expressed Interleukin-1 Receptor I

Division of Endocrinology, Diabetes, and Nutrition (M.B.-S., S.B., D.T.M., R.P., J.A.E., M.Y.D.) and Center for Integrated Human Physiology, University Hospital Zurich, CH-8091 Zurich, Switzerland; Gene Expression Unit (S.D., F.C.S.), Department of Molecular Cell Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Department of Genetic Medicine and Development (K.B.), University of Geneva, 1211 Geneva 4, Switzerland; and Université Lille Nord de France (J.K.-C., F.P.), Université de Droits et de Santé de Lille, Centre Hospitalier Universitaire Lille, Institut National de la Santé et de la Recherche Médicale Unité 859, Biotherapies for Diabetes, F-59000 Lille, France

Address all correspondence and requests for reprints to: Marianne Böni-Schnetzler, Ph.D., Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: marianne. boeni{at}usz.ch.

Islets of patients with type 2 diabetes mellitus (T2DM) display features of an inflammatory process including elevated levels of the cytokine IL-1β, various chemokines, and macrophages. IL-1β is a master regulator of inflammation, and IL-1 receptor type I (IL-1RI) blockage improves glycemia and insulin secretion in humans with T2DM and in high-fat-fed mice pointing to a pivotal role of IL-1RI activity in intra-islet inflammation. Given the association of dyslipidemia and T2DM, we tested whether free fatty acids (FFA) promote the expression of proinflammatory factors in human and mouse islets and investigated a role for the IL-1RI in this response. A comparison of 22 mouse tissues revealed the highest IL-1RI expression levels in islets and MIN6 β-cells. FFA induced IL-1β, IL-6, and IL-8 in human islets and IL-1β and KC in mouse islets. Elevated glucose concentrations enhanced FFA-induced proinflammatory factors in human islets. Blocking the IL-1RI with the IL-1R antagonist (IL-1Ra) strongly inhibited FFA-mediated expression of proinflammatory factors in human and mouse islets. Antibody inhibition of IL-1β revealed that FFA stimulated IL-1RI activity via the induction of the receptor ligand. FFA-induced IL-1β and KC expression in mouse islets was completely dependent on the IL-1R/Toll-like receptor (TLR) docking protein Myd88 and partly dependent on TLR2 and -4. Activation of TLR2 in purified human β-cells and islets stimulated the expression of proinflammatory factors, and IL-1RI activity increased the TLR2 response in human islets. We conclude that FFA and TLR stimulation induce proinflammatory factors in islets and that IL-1RI engagement results in signal amplification.

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