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.
Footnotes
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This work was supported in part by a Grant-in-Aid for Encouragement of Young Scientists from the Japan Society for the Promotion of Science (to A.M.), and by the Pancreas Research Foundation of Japan (to A.M.).
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DOI: 10.1124/jpet.102.040287
- Abbreviations:
- PSC
- pancreatic stellate cell
- α-SMA
- α-smooth muscle actin
- MAP kinase
- mitogen-activated protein kinase
- SB203580
- 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole
- SB202190
- 4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole
- IL
- interleukin
- PDGF
- platelet-derived growth factor
- MAPKAPK-2
- MAP kinase-activated protein kinase-2
- IκB
- inhibitor of nuclear factor κB
- SB202474
- 4-(ethyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)1H-imidazole
- MCP-1
- monocyte chemoattractant protein-1
- NF-κB
- nuclear factor κB
- Received June 13, 2002.
- Accepted September 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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