Calcium has a permissive role in interleukin-1β-induced c-jun n-terminal kinase activation in insulin-secreting cells

Joachim Størling, Sergei V. Zaitsev, Iouri L. Kapelioukh, Allan E. Karlsen, Nils Billestrup, Per Olof Berggren, Thomas Mandrup-Poulsen

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1β-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic β-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1β activation of JNK in β-cells are largely unknown. In this study, we investigated whether Ca2+ plays a role for IL-1β-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-1β-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1β-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1β-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 βTC3 cells. Ca2+ influx, specifically via L-type but not T-type channels, contributed to IL-1β activation of JNK. Activation of p38 and ERK in response to IL-1β 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-1β-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-1β-stimulated c-jun phosphorylation in INS-1 or βTC3 cells. Our data suggest that Ca2+ plays a permissive role in IL-1β activation of the JNK signaling pathway in insulin-secreting cells.

Original languageEnglish (US)
Pages (from-to)3026-3036
Number of pages11
JournalEndocrinology
Volume146
Issue number7
DOIs
StatePublished - Jul 1 2005

    Fingerprint

ASJC Scopus subject areas

  • Endocrinology

Cite this

Størling, J., Zaitsev, S. V., Kapelioukh, I. L., Karlsen, A. E., Billestrup, N., Berggren, P. O., & Mandrup-Poulsen, T. (2005). Calcium has a permissive role in interleukin-1β-induced c-jun n-terminal kinase activation in insulin-secreting cells. Endocrinology, 146(7), 3026-3036. https://doi.org/10.1210/en.2005-0036