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

Interleukin (IL)-1 beta, a multifunctional cytokine, is associated with inf lammatory gastric mucosa, but the responses of gastric epithelial cells sti mulated by IL-1 beta are not known. We determined whether IL-1 beta activat es the two subfamilies of mitogen-activated protein (MAP) kinases, extracel lular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs) , in rat gastric epithelial cells (RGM1) using in-gel kinase assays. In add ition, we examined the mechanism(s) underlying their signaling pathways and the effect on proliferation of these cells, IL-1 beta (0-5 x 10(3) pg/ml) dose dependently induced activation of ERKs (p44ERK and p42ERK) and JNKs (p 46JNK and p55JNK) in RGM1 cells; maximal activities were attained with 1,00 0 pg/ml of IL-1 beta. These activities were increased with time, and were m aximal 20 min after stimulation with IL-1 beta (100 pg/ml). Pretreatment wi th neutralizing antibody against IL-1 beta inhibited IL-1 beta-induced acti vation of ERKs and JNKs. Genistein (100 mu M), a tyrosine kinase inhibitor, and GF109203X (2 mu M), a protein kinase C inhibitor, inhibited the IL-1 b eta-induced activation of ERKs and JNKs, Six- hour pre-incubation with IL-1 beta 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-1 beta activated ERKs and JNKs in rat gastric epithelial cells and inhibited cell proliferation, possibly via the specific receptor for IL-1 beta. Activ ation of MAP kinases by IL-1 beta may be mediated by tyrosine kinase and pr otein kinase C. Copyright (C) 2000 S. Karger AG, Basel.