The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells

• Published in: Diabetes (New York, N.Y.) Vol. 49; no. 9; pp. 1468 - 1476
• Main Authors: AMMENDRUP, A, MAILLARD, A, NIELSEN, K, ANDERSEN, N. A, SERUP, P, MADSEN, O. D, MANDRUP-POULSEN, T, BONNY, C
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-09-2000
• Subjects: Ageing, cell death; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Cell death; Cell Differentiation - physiology; Cell Line; Cell physiology; Cytokines; Diabetes; Fundamental and applied biological sciences. Psychology; Heat shock proteins; Homeodomain Proteins - metabolism; Humans; Interleukin-1; Interleukin-1 - pharmacology; Intracellular Signaling Peptides and Proteins; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - physiology; JNK Mitogen-Activated Protein Kinases; Kinases; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - pharmacology; Molecular and cellular biology; Nitric oxide; Nitric Oxide - metabolism; p38 Mitogen-Activated Protein Kinases; Pancreatic beta cells; Physiological aspects; Protein-Serine-Threonine Kinases - metabolism; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Trans-Activators - metabolism; Transfection; Cell line; B-Cell; Cell death; Cytokine; Langerhans islet; Interleukin 1; Differentiation; Protooncogene; Endocrine pancreas; Apoptosis; Immediate early gene
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.49.9.1468

The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating
pancreatic beta-cells.
A Ammendrup ,
A Maillard ,
K Nielsen ,
N Aabenhus Andersen ,
P Serup ,
O Dragsbaek Madsen ,
T Mandrup-Poulsen and
C Bonny
Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark.
Abstract
To characterize the differentiation events that selectively target insulin-producing cells to interleukin (IL)-1beta-induced
apoptosis, we studied IL-1beta signaling via mitogen-activated protein kinase (MAPK) and stress-activated protein kinase in
2 pancreatic endocrine cell lines. We studied the glucagon-secreting AN-glu cell line and the insulin and the islet amyloid
polypeptide-producing beta-cell line (AN-ins cells), which is derived by stable transfection of AN-glu cells with the transcription
factor pancreatic duodenal homeobox factor-1. AN-ins cells were more sensitive to the cytotoxic action of IL-1beta. This increased
sensitivity was not associated with a more pronounced IL-l-induced nitric oxide production in AN-ins cells, but it correlated
with a more marked activation of the 3 MAPKs extracellular signal-regulated kinases (ERKs)-1/2, c-Jun NH2-terminal kinase
(JNK), and p38 MAPK (p38). This led to increased phosphorylation of the transcription factors c-Jun, Elk-1, and ATF2 and of
heat shock protein 25. Inhibition of ERK-1/2 and p38 did not prevent but aggravated IL-1beta-induced cell death. In contrast,
inhibition of JNK by transfection with the dominant negative inhibitor of the JNK-binding domain prevented apoptosis in both
cell types. Cell death could be elicited by overexpressing the catalytic domain of MAPK kinase kinase 1, a specific activator
of JNK and nuclear factor-kappaB, which does not recruit ERK-1/2 or p38. Coactivation of ERK-1/2 with JNK did not prevent
apoptosis. In conclusion, increased MAPK signaling in response to IL-1beta may represent a novel molecular marker of beta-cell
differentiation. JNK inhibition represents an effective means of preventing IL-1beta-activated beta-cell destruction.