Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway.
OBJECTIVE
The pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) generates pancreatic beta-cells apoptosis mainly through activation of the c-Jun NH(2)-terminal kinase (JNK) pathway. This study was designed to investigate whether the long-acting agonist of the hormone glucagon-like peptide 1 (GLP-1) receptor exendin-4 (ex-4), which mediates protective effects against cytokine-induced beta-cell apoptosis, could interfere with the JNK pathway.


METHODS
Isolated human, rat, and mouse islets and the rat insulin-secreting INS-1E cells were incubated with ex-4 in the presence or absence of IL-1 beta. JNK activity was assessed by solid-phase JNK kinase assay and quantification of c-Jun expression. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei.


RESULTS
Ex-4 inhibited induction of the JNK pathway elicited by IL-1 beta. This effect was mimicked with the use of cAMP-raising agents isobutylmethylxanthine and forskolin and required activation of the protein kinase A. Inhibition of the JNK pathway by ex-4 or IBMX and forskolin was concomitant with a rise in the levels of islet-brain 1 (IB1), a potent blocker of the stress-induced JNK pathway. In fact, ex-4 as well as IBMX and forskolin induced expression of IB1 at the promoter level through cAMP response element binding transcription factor 1. Suppression of IB1 levels with the use of RNA interference strategy impaired the protective effects of ex-4 against apoptosis induced by IL-1 beta.


CONCLUSIONS
The data establish the requirement of IB1 in the protective action of ex-4 against apoptosis elicited by IL-1 beta and highlight the GLP-1 mimetics as new potent inhibitors of the JNK signaling induced by cytokines.
Ferdaoussi
Mourad
M
Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Abdelli
Saida
S
Yang
Jiang-Yan
JY
Cornu
Marion
M
Niederhauser
Guy
G
Favre
Dimitri
D
Widmann
Christian
C
Regazzi
Romano
R
Thorens
Bernard
B
Waeber
Gérard
G
Abderrahmani
Amar
A
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D014688:Venoms / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D048031:JNK Mitogen-Activated Protein Kinases