Cytokine-induced osteoprotegerin expression protects pancreatic beta cells through p38 mitogen-activated protein kinase signalling against cell death.
OBJECTIVE
Pro-inflammatory cytokines play a crucial role in immune-mediated beta cell destruction, an essential mechanism in the pathogenesis of type 1 diabetes mellitus. Microarray analysis recently identified osteoprotegerin (OPG; now known as tumour necrosis factor receptor superfamily, member 11b [TNFRSF11B]) as a cytokine-induced gene in beta cells. The aim of the present study was to characterise the functional role and signalling pathways of OPG that are involved in cytokine-induced beta cell death.


METHODS
As cellular models, the rat beta cell line INS-1E and human primary pancreatic islets were employed. The effects of IL-1beta and TNF-alpha on OPG expression were characterised by northern blot and immunoassay. The effect of OPG on beta cell survival was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Signalling pathways were evaluated by western blot analysis using antibodies against p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2.


RESULTS
The INS-1E cell line and primary pancreatic islets expressed OPG mRNA and secreted OPG protein, both of which were enhanced by IL-1beta and TNF-alpha. Exposure to IL-1beta resulted in sustained phosphorylation of p38 MAPK in INS-1E cells and subsequent cell death. Administration of exogenous OPG prevented both IL-1beta-induced beta cell death and sustained p38 MAPK phosphorylation.


CONCLUSIONS
Our data indicate that cytokine-induced production of OPG may protect beta cells from further damage. This protective effect is, at least in part, mediated through inhibition of p38 MAPK phosphorylation. Thus OPG is an autocrine or paracrine survival factor for beta cells.
Schrader
J
J
Division of Gastroenterology & Endocrinology, Department of Medicine, Philipps-University, Baldingerstrasse, 35033 Marburg, Germany.
Rennekamp
W
W
Niebergall
U
U
Schoppet
M
M
Jahr
H
H
Brendel
M D
MD
Hörsch
D
D
Hofbauer
L C
LC
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000502:physiology*; D053583:Interleukin-1beta / Q000494:pharmacology; D007700:Kinetics; D053244:Osteoprotegerin / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016207:Cytokines; D053583:Interleukin-1beta; D053244:Osteoprotegerin; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases