Role of p38 mitogen-activated protein kinase (p38 MAPK) in cytokine-induced rat islet cell apoptosis

Biochem Pharmacol. 2001 Jun 15;61(12):1561-9. doi: 10.1016/s0006-2952(01)00605-0.


The signaling pathways mediating nitric oxide production and apoptosis in pancreatic beta-cells are not fully understood. We investigated cytokine-induced protein phosphorylation events in insulin-producing cells and evaluated their role in inducible nitric oxide synthase (iNOS) induction and cell death. Interleukin-1beta (IL-1beta), but not interferon-gamma (IFN-gamma), induced phosphorylation of p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, and mitogen- and stress-activated protein kinase 1 (MSK1) in rat insulin-producing RINm5F cells. This was paralleled by an increased phosphorylation of the transcription factors activating transcription factor-2 (ATF-2) and cAMP-responsive element-binding protein (CREB). The p38 inhibitor SB203580 prevented cytokine-induced phosphorylation of CREB and MSK1, but not of ATF-2. IFN-gamma induced the phosphorylation of signal transducer and activator of transcription 1. The combination of IL-1beta and IFN-gamma increased both apoptosis and necrosis in rat islet cells. SB203580, but not the extracellular signal-regulated kinase inhibitor PD98059, partially prevented cytokine-induced apoptosis, an effect that was not associated with reduced nitrite production or lowered iNOS expression. In conclusion, cytokine-induced p38 activation participates in beta-cell apoptosis, possibly by a nitric oxide-independent mechanism or by enhancing the sensitivity to nitric oxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cells, Cultured
  • Cytokines / pharmacology*
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Imidazoles / pharmacology
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / drug effects
  • Male
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase Type II
  • Phosphorylation
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • STAT1 Transcription Factor
  • Signal Transduction
  • Trans-Activators / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • p38 Mitogen-Activated Protein Kinases


  • Cytokines
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Interleukin-1
  • Pyridines
  • STAT1 Transcription Factor
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one