title: Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells.
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 alpha-smooth muscle actin, alpha1(I) procollagen, and prolyl 4-hydroxylase (alpha) genes, and monocyte chemoattractant protein-1 production were evaluated. Interleukin-1beta 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 alpha-smooth muscle actin protein expression, and alpha1(I) procollagen and prolyl 4-hydroxylase (alpha) 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.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. amasamune@int3.med.tohoku.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satoh
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sakai
authors.forename: Akihiko
authors.initials: A
authors.lastname: Satoh
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004586:Electrophoresis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011347:Procollagen / Q000096:biosynthesis; D011393:Procollagen-Proline Dioxygenase / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000199:Actins; D000730:Androstadienes; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D010982:Platelet-Derived Growth Factor; D011347:Procollagen; D011393:Procollagen-Proline Dioxygenase; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole