Journal
WORLD JOURNAL OF GASTROENTEROLOGY
Volume 12, Issue 9, Pages 1392-1396Publisher
BAISHIDENG PUBLISHING GROUP INC
DOI: 10.3748/wjg.v12.i9.1392
Keywords
TIMMP-1; JNK; p38; signal transduction; interleukin-1 beta; hepatic stellate cells
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AIM: To study the relationship between interleukin-1beta (IL-1 beta) up-regulating tissue inhibitor of matrix metalloproteinase-1 (TIMMP-1) mRNA expression and phosphorylation of both c-jun N-terminal kinase (JNK) and p38 in rat hepatic stellate cells (HSC). METHODS: RT-PCR was performed to measure the expression of TIMMP-1 mRNA in rat HSC. Western blot was performed to measure IL-1 beta-induced INK and p38 activities in rat HSC. RESULTS: TIMMP-1 mRNA expression (1.191 +/- 0.079) was much higher after treatment with IL-10 (10 ng/mL) for 24 h than in control group (0.545 +/- 0.091) (P<0.01). IL-1 beta activated JNK and p38 in a time-dependent manner. After stimulation with IL-1 beta for 0, 5, 15, 30, 60 and 120 min, the INK activity was 0.982 +/- 0.299, 1.501 +/- 0.720, 2.133 +/- 0.882, 3.360 +/- 0.452, 2.181 +/- 0.789, and 1.385 +/- 0.368, respectively. There was a significant difference in INK activity at 15 min (P < 0.01), 30 min (P < 0.01) and 60 min (P < 0.01) in comparison to that at 0 min. The p38 activity was 1.061 +/- 0.310, 2.050 +/- 0.863, 2.380 +/- 0.573, 2.973 +/- 0.953, 2.421 +/- 0.793, and 1.755 +/- 0.433 at the 6 time points (0, 5, 15, 30, 60 and 120 min) respectively. There was a significant difference in p38 activity at 5 min (P < 0.05), 15 min (P < 0.01), 30 min (P<0.01) and 60 min (P < 0.01) compared to that at 0 min. TIMMP-1 mRNA expression trended to decrease in 3 groups pretreated with different concentrations of SP600125 (10 mu mol/L, 1.022 +/- 0.113; 20 mu mol/L, 0.869 +/- 0.070; 40 mu mol/L, 0.666 +/- 0.123). Their decreases were all significant (P < 0.05, P < 0.01, P < 0.01) in comparison to control group (without SP600125 treatment, 1.163 +/- 0.107). In the other 3 groups pretreated with different concentrations of SB203580 (10 mu mol/L, 1.507 +/- 0.099; 20 mu mol/L, 1.698 +/- 0.107; 40 mu mol/L, 1.857 +/- 0.054), the expression of TIMMP-1 mRNA increased. Their levels were higher than those in the control group (without SB203580 treatment, 1.027 +/- 0.061) with a significant statistical significance (P < 0.01). CONCLUSION: IL-1 beta has a direct action on hepatic fibrosis by up-regulating TIMMP-1 mRNA expression in rat HSC. JNK and p38 mitogen-activated protein kinases (MAPKs) are involved in IL-1 beta-induced TIMMP-1 gene expression, and play a distinct role in this process, indicating that p38 and JNK pathways cooperatively mediate TIMP-1 mRNA expression in rat HSC. (C) 2006 The WJG Press. All rights reserved.
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