This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Størling, J. Articles by Mandrup-Poulsen, T. Search for Related Content PubMed PubMed Citation Articles by Størling, J. Articles by Mandrup-Poulsen, T.

Calcium Has a Permissive Role in Interleukin-1ß-Induced c-Jun N-Terminal Kinase Activation in Insulin-Secreting Cells

Laboratory for ß-Cell Biology (J.S., A.E.K, N.B., T.M.-P.), Steno Diabetes Center, DK-2820 Gentofte, Denmark; The Rolf Luft Center for Diabetes Research (S.V.Z., I.L.K., P.-O.B., T.M.-P.), Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden; and Belozersky Institute of Physico-Chemical Biology (S.V.Z.), Moscow State University, Moscow 119899, Russia

Address all correspondence and requests for reprints to: Thomas Mandrup-Poulsen, M.D., D.M.Sc., Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. E-mail: tmpo{at}steno.dk; or Joachim Størling, M.Sc., Steno Diabetes Center, Niels Steensensvej 8, NSPP, DK-2820 Gentofte, Denmark. E-mail: jstq{at}steno.dk.

The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1ß-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic ß-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1ß activation of JNK in ß-cells are largely unknown. In this study, we investigated whether Ca²⁺ plays a role for IL-1ß-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 Ca²⁺ channels suppressed IL-1ß-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1ß-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1ß-induced in vitro kinase activity toward c-jun after collective L- and T-type Ca²⁺ channel blockade was confirmed in primary rat and ob/ob mouse islets and in mouse ßTC3 cells. Ca²⁺ influx, specifically via L-type but not T-type channels, contributed to IL-1ß activation of JNK. Activation of p38 and ERK in response to IL-1ß was also dependent on L-type Ca²⁺ influx. Membrane depolarization by KCl, exposure to high glucose, treatment with Ca²⁺ ionophore A23187, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca²⁺ ATPase, all caused an amplification of IL-1ß-induced JNK activation in INS-1 cells. Finally, a chelator of intracellular free Ca²⁺ [bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid-acetoxymethyl], an inhibitor of calmodulin (W7), and inhibitors of Ca²⁺/calmodulin-dependent kinase (KN62 and KN93) partially reduced IL-1ß-stimulated c-jun phosphorylation in INS-1 or ßTC3 cells. Our data suggest that Ca²⁺ plays a permissive role in IL-1ß activation of the JNK signaling pathway in insulin-secreting cells.

This article has been cited by other articles:

				K. Maedler, F. T. Schulthess, C. Bielman, T. Berney, C. Bonny, M. Prentki, M. Y. Donath, and R. Roduit Glucose and leptin induce apoptosis in human {beta}-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases FASEB J, June 1, 2008; 22(6): 1905 - 1913. [Abstract] [Full Text] [PDF]

				M. Y. Donath, J. Storling, L. A. Berchtold, N. Billestrup, and T. Mandrup-Poulsen Cytokines and {beta}-Cell Biology: from Concept to Clinical Translation Endocr. Rev., May 1, 2008; 29(3): 334 - 350. [Abstract] [Full Text] [PDF]