Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells

Atsushi Masamune, Masahiro Satoh, Kazuhiro Kikuta, Yoshitaka Sakai, Akihiko Satoh, Tooru Shimosegawa

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

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 α-smooth muscle actin, α1(I) procollagen, and prolyl 4-hydroxylase (α) genes, and monocyte chemoattractant protein-1 production were evaluated. Interleukin-1β 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 α-smooth muscle actin protein expression, and α1(I) procollagen and prolyl 4-hydroxylase (α) 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.

Original languageEnglish
Pages (from-to)8-14
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume304
Issue number1
DOIs
Publication statusPublished - 2003 Jan 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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