title: Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I.
abstract: Islets of patients with type 2 diabetes mellitus (T2DM) display features of an inflammatory process including elevated levels of the cytokine IL-1beta, various chemokines, and macrophages. IL-1beta 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 beta-cells. FFA induced IL-1beta, IL-6, and IL-8 in human islets and IL-1beta 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-1beta revealed that FFA stimulated IL-1RI activity via the induction of the receptor ligand. FFA-induced IL-1beta 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 beta-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.
authors.affiliation: Division of Endocrinology, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. marianne. boeni@usz.ch
authors.forename: Marianne
authors.initials: M
authors.lastname: Böni-Schnetzler
authors.forename: Simone
authors.initials: S
authors.lastname: Boller
authors.forename: Sarah
authors.initials: S
authors.lastname: Debray
authors.forename: Karim
authors.initials: K
authors.lastname: Bouzakri
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meier
authors.forename: Richard
authors.initials: R
authors.lastname: Prazak
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.forename: Jan A
authors.initials: JA
authors.lastname: Ehses
authors.forename: Frans C
authors.initials: FC
authors.lastname: Schuit
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D005230:Fatty Acids, Nonesterified; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016209:Interleukin-8; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4