Increased mitogen-activated protein kinase activities stimulated with interleukin-1-beta and mechanism(s) of the kinase signaling pathways in rat gastric epithelial cells

Digestion. 2000;61(1):30-8. doi: 10.1159/000007733.


Interleukin (IL)-1beta, a multifunctional cytokine, is associated with inflammatory gastric mucosa, but the responses of gastric epithelial cells stimulated by IL-1beta are not known. We determined whether IL-1beta activates the two subfamilies of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinases (ERKs) and c-Jun NH(2)-terminal kinases (JNKs), in rat gastric epithelial cells (RGM1) using in-gel kinase assays. In addition, we examined the mechanism(s) underlying their signaling pathways and the effect on proliferation of these cells. IL-1beta (0-5 x 10(3) pg/ml) dose dependently induced activation of ERKs (p44ERK and p42ERK) and JNKs (p46JNK and p55JNK) in RGM1 cells; maximal activities were attained with 1,000 pg/ml of IL-1beta. These activities were increased with time, and were maximal 20 min after stimulation with IL-1beta (100 pg/ml). Pretreatment with neutralizing antibody against IL-1beta inhibited IL-1beta-induced activation of ERKs and JNKs. Genistein (100 microM), a tyrosine kinase inhibitor, and GF109203X (2 microM), a protein kinase C inhibitor, inhibited the IL-1beta-induced activation of ERKs and JNKs. Six- hour pre-incubation with IL-1beta inhibited proliferation of these cells by 40% at 24 h of incubation, but the inhibition was recovered at 48 h. These findings suggest that IL-1beta activated ERKs and JNKs in rat gastric epithelial cells and inhibited cell proliferation, possibly via the specific receptor for IL-1beta. Activation of MAP kinases by IL-1beta may be mediated by tyrosine kinase and protein kinase C.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cells, Cultured / drug effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / drug effects*
  • Epithelial Cells / enzymology
  • Gastric Mucosa / drug effects*
  • Gastric Mucosa / enzymology
  • Genistein / pharmacology
  • Indoles / pharmacology
  • Interleukin-1 / pharmacology*
  • JNK Mitogen-Activated Protein Kinases
  • Maleimides / pharmacology
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Precipitin Tests
  • Protein Kinase Inhibitors
  • Rats
  • Signal Transduction / physiology*


  • Enzyme Inhibitors
  • Indoles
  • Interleukin-1
  • Maleimides
  • Protein Kinase Inhibitors
  • Genistein
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • bisindolylmaleimide I