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 Citations (Scopus)

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

Fingerprint

Insulin-Secreting Cells
Interleukin-1
Phosphotransferases
JNK Mitogen-Activated Protein Kinases
Calcium
Phosphorylation
Glucose
Reticulum
Calcium-Calmodulin-Dependent Protein Kinases
Thapsigargin
Calcium-Transporting ATPases
Ionophores
Calcimycin
Calmodulin
Chelating Agents
Type 1 Diabetes Mellitus
Immunoblotting
Type 2 Diabetes Mellitus
Cultured Cells
Pharmacology

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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

Calcium has a permissive role in interleukin-1β-induced c-jun n-terminal kinase activation in insulin-secreting cells. / Størling, Joachim; Zaitsev, Sergei V.; Kapelioukh, Iouri L.; Karlsen, Allan E.; Billestrup, Nils; Berggren, Per Olof; Mandrup-Poulsen, Thomas.

In: Endocrinology, Vol. 146, No. 7, 01.07.2005, p. 3026-3036.

Research output: Contribution to journalArticle

Størling, J, Zaitsev, SV, Kapelioukh, IL, Karlsen, AE, Billestrup, N, Berggren, PO & Mandrup-Poulsen, T 2005, 'Calcium has a permissive role in interleukin-1β-induced c-jun n-terminal kinase activation in insulin-secreting cells', Endocrinology, vol. 146, no. 7, pp. 3026-3036. https://doi.org/10.1210/en.2005-0036
Størling J, Zaitsev SV, Kapelioukh IL, Karlsen AE, Billestrup N, Berggren PO et al. Calcium has a permissive role in interleukin-1β-induced c-jun n-terminal kinase activation in insulin-secreting cells. Endocrinology. 2005 Jul 1;146(7):3026-3036. https://doi.org/10.1210/en.2005-0036
Størling, Joachim ; Zaitsev, Sergei V. ; Kapelioukh, Iouri L. ; Karlsen, Allan E. ; Billestrup, Nils ; Berggren, Per Olof ; Mandrup-Poulsen, Thomas. / Calcium has a permissive role in interleukin-1β-induced c-jun n-terminal kinase activation in insulin-secreting cells. In: Endocrinology. 2005 ; Vol. 146, No. 7. pp. 3026-3036.
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