451. Calcium has a permissive role in interleukin-1beta-induced c-jun N-terminal kinase activation in insulin-secreting cells.
- Author
-
Størling J, Zaitsev SV, Kapelioukh IL, Karlsen AE, Billestrup N, Berggren PO, and Mandrup-Poulsen T
- Subjects
- Animals, Calcium metabolism, Calcium Channel Blockers pharmacology, Cell Line, Drug Synergism, Enzyme Activation drug effects, Enzyme Activation physiology, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Insulin Secretion, Intracellular Membranes metabolism, Islets of Langerhans enzymology, Mibefradil pharmacology, Mice, NF-kappa B metabolism, Nimodipine pharmacology, Rats, Rats, Inbred WF, Signal Transduction drug effects, p38 Mitogen-Activated Protein Kinases metabolism, Calcium physiology, Insulin metabolism, Interleukin-1 pharmacology, Islets of Langerhans metabolism, JNK Mitogen-Activated Protein Kinases metabolism
- Abstract
The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1beta-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic beta-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1beta activation of JNK in beta-cells are largely unknown. In this study, we investigated whether Ca(2+) plays a role for IL-1beta-induced JNK activation. In insulin-secreting rat INS-1 cells cultured in the presence of 11 mm glucose, combined pharmacological blockade of L- and T-type Ca(2+) channels suppressed IL-1beta-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1beta-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1beta-induced in vitro kinase activity toward c-jun after collective L- and T-type Ca(2+) channel blockade was confirmed in primary rat and ob/ob mouse islets and in mouse betaTC3 cells. Ca(2+) influx, specifically via L-type but not T-type channels, contributed to IL-1beta activation of JNK. Activation of p38 and ERK in response to IL-1beta was also dependent on L-type Ca(2+) influx. Membrane depolarization by KCl, exposure to high glucose, treatment with Ca(2+) ionophore A23187, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca(2+) ATPase, all caused an amplification of IL-1beta-induced JNK activation in INS-1 cells. Finally, a chelator of intracellular free Ca(2+) [bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid-acetoxymethyl], an inhibitor of calmodulin (W7), and inhibitors of Ca(2+)/calmodulin-dependent kinase (KN62 and KN93) partially reduced IL-1beta-stimulated c-jun phosphorylation in INS-1 or betaTC3 cells. Our data suggest that Ca(2+) plays a permissive role in IL-1beta activation of the JNK signaling pathway in insulin-secreting cells.
- Published
- 2005
- Full Text
- View/download PDF