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Vol. 304, Issue 1, 8-14, January 2003
Division of Gastroenterology, Tohoku University Graduate School of
Medicine, Sendai, Japan
Activated pancreatic stellate cells (PSCs) have recently been
implicated in the pathogenesis of pancreatic fibrosis and inflammation. However, the signal transduction pathways in PSCs remain largely unknown. We examined the role of p38 mitogen-activated protein (MAP)
kinase in the activation of PSCs. PSCs were isolated from rat pancreas
tissue and used in their culture-activated, myofibroblast-like phenotype. Activation of p38 MAP kinase was determined by Western blotting using anti-phosphospecific antibody. The effects of two p38
MAP kinase inhibitors,
4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) and
4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole (SB202190), on the parameters of PSC activation, including
proliferation, expression of 
-smooth muscle actin, 1(I)
procollagen, and prolyl 4-hydroxylase () genes, and monocyte
chemoattractant protein-1 production were evaluated. Interleukin-1
and platelet-derived growth factor-BB activated p38 MAP kinase.
Platelet-derived growth factor-induced PSC proliferation was inhibited
by SB203580 and SB202190. These reagents decreased -smooth muscle
actin protein expression, and 1(I) procollagen and prolyl
4-hydroxylase () mRNA levels. Treatment with these p38 MAP kinase
inhibitors also resulted in inhibition of monocyte chemoattractant
protein-1 expression. In addition, SB203580 inhibited spontaneous
activation of freshly isolated PSCs in culture on plastic. Thus,
inhibition of p38 MAP kinase modulated profibrogenic and
proinflammatory actions in PSCs, implying a potential application of
p38 MAP kinase inhibitors for the treatment of pancreatic fibrosis and inflammation.
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