A subset of human pancreatic beta cells express functional CD14 receptors: a signaling pathway for beta cell-related glycolipids, sulfatide and ß-galactosylceramide

TY - JOUR

T1 - A subset of human pancreatic beta cells express functional CD14 receptors: a signaling pathway for beta cell-related glycolipids, sulfatide and ß-galactosylceramide

AU - Østerbye, Thomas

AU - Funda, David P

AU - Fundová, Petra

AU - Månsson, Jan-Eric

AU - Tlaskalová-Hogenová, Helena

AU - Buschard, Karsten

N1 - Copyright © 2010 John Wiley & Sons, Ltd.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Background: T1DM is a T-cell-mediated autoimmune disease targeting insulin-producing beta-cells. Multiple factors may contribute to the development of T1DM. Among these, the metabolic state of beta-cells and pro-inflammatory cytokines, produced by infiltrating immune cells, have been implicated in the precipitation of T1DM. Methods and Results: In this study, confocal immunofluorescence microscopy of human pancreata revealed a distinct subset of beta-cells expressing the innate LPS co-receptor CD14. Human islets expressed fully functional CD14 as LPS stimulation led to a dose-dependent secretion of tumour necrosis factor (TNFα), interleukin (IL)-1β and IL-8, which were substantially inhibited by a blocking anti-CD14 mAb. In addition, LPS stimulation impaired the glucose-mediated insulin secretion in rat islets. β-GalCer and sulfatide, glycolipids that are related to insulin processing and secretion, are possibly interacting with the CD14 receptor complex. β-GalCer had an LPS-like, serum- and CD14-dependent effect on the induction of pro-inflammatory cytokines in a human monocyte cell line. In contrast, the LPS-mediated cytokine production was inhibited by sulfatide. Human islets also responded to β-GalCer (10 μg/mL) by secreting TNFα IL-1β and IL-8, whereas sulfatide partly inhibited the effect of LPS. Conclusions: A subset of human beta-cells expresses functional CD14 receptor and thus is able to recognize both exogenous bacterial (LPS) as well as endogenous ligands (e.g. glycolipids of beta-cell origin). The CD14 expression on a subset of human beta-cells may play a role in the innate surveillance of the endocrine environment but may also contribute to innate immune mechanisms in the early stages of beta-cell aggression.

AB - Background: T1DM is a T-cell-mediated autoimmune disease targeting insulin-producing beta-cells. Multiple factors may contribute to the development of T1DM. Among these, the metabolic state of beta-cells and pro-inflammatory cytokines, produced by infiltrating immune cells, have been implicated in the precipitation of T1DM. Methods and Results: In this study, confocal immunofluorescence microscopy of human pancreata revealed a distinct subset of beta-cells expressing the innate LPS co-receptor CD14. Human islets expressed fully functional CD14 as LPS stimulation led to a dose-dependent secretion of tumour necrosis factor (TNFα), interleukin (IL)-1β and IL-8, which were substantially inhibited by a blocking anti-CD14 mAb. In addition, LPS stimulation impaired the glucose-mediated insulin secretion in rat islets. β-GalCer and sulfatide, glycolipids that are related to insulin processing and secretion, are possibly interacting with the CD14 receptor complex. β-GalCer had an LPS-like, serum- and CD14-dependent effect on the induction of pro-inflammatory cytokines in a human monocyte cell line. In contrast, the LPS-mediated cytokine production was inhibited by sulfatide. Human islets also responded to β-GalCer (10 μg/mL) by secreting TNFα IL-1β and IL-8, whereas sulfatide partly inhibited the effect of LPS. Conclusions: A subset of human beta-cells expresses functional CD14 receptor and thus is able to recognize both exogenous bacterial (LPS) as well as endogenous ligands (e.g. glycolipids of beta-cell origin). The CD14 expression on a subset of human beta-cells may play a role in the innate surveillance of the endocrine environment but may also contribute to innate immune mechanisms in the early stages of beta-cell aggression.

KW - Adult

KW - Animals

KW - Antigens, CD14

KW - Cells, Cultured

KW - Female

KW - Galactosylceramides

KW - Glycolipids

KW - Humans

KW - Insulin-Secreting Cells

KW - Interleukin-8

KW - Lipopolysaccharides

KW - Male

KW - Rats

KW - Signal Transduction

KW - Sulfoglycosphingolipids

KW - Tumor Necrosis Factor-alpha

U2 - 10.1002/dmrr.1134

DO - 10.1002/dmrr.1134

M3 - Journal article

C2 - 20949640

SN - 1520-7560

VL - 26

SP - 656

EP - 667

JO - Diabetes - Metabolism: Research and Reviews (Online Edition)

JF - Diabetes - Metabolism: Research and Reviews (Online Edition)

IS - 8

ER -