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


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.
Osterbye
Thomas
T
Bartholin Instituttet, Rigshospitalet, Biocenter Copenhagen, Copenhagen N, Denmark.
Funda
David P
DP
Fundová
Petra
P
Månsson
Jan-Eric
JE
Tlaskalová-Hogenová
Helena
H
Buschard
Karsten
K
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005699:Galactosylceramides / Q000378:metabolism; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051381:Rats; D015398:Signal Transduction; D013433:Sulfoglycosphingolipids / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D005699:Galactosylceramides; D006017:Glycolipids; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D013433:Sulfoglycosphingolipids; D014409:Tumor Necrosis Factor-alpha