Induced secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) in vivo and in vitro by hepatotoxin rubratoxin B.
To elucidate the mechanism of rubratoxin B toxicity, we investigated rubratoxin B-induced secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) in mice and cultured cells; we also documented the involvement of stress-activated MAP kinases (c-Jun-N-terminal kinases [JNKs] and p38s) in this process. Rubratoxin B significantly (P<0.05) induced serum TIMP-1 levels in mice. Because TIMP-1 is thought to play a crucial role in the process of liver fibrosis, rubratoxin B may cause liver fibrosis. Rubratoxin B enhanced TIMP-1 secretion in HepG2 cells to a peak level of approximately 40 microg/ml. The amount of TIMP-1 mRNA increased with the duration of rubratoxin B treatment; and this hepatotoxin appears to induce TIMP-1 secretion through a transcriptional control mechanism. Unlike similar treatment with rubratoxin B and JNK inhibitor, concomitant treatment with rubratoxin B and p38 inhibitor increased rubratoxin B-induced TIMP-1 secretion, suggesting that p38s (but not JNKs) antagonize this process. In addition, treatment with p38 inhibitor slightly increased the amount of rubratoxin B-induced TIMP-1 mRNA, suggesting that p38s control rubratoxin B-induced TIMP-1 secretion chiefly post-transcriptionally. In this study, we showed that rubratoxin B induces TIMP-1 production in vivo and in vitro and that p38s antagonize rubratoxin B-induced TIMP-1 secretion.
National Food Research Institute, 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan. nagasima@nfri.affrc.go.jp
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Nagashima
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Maeda-Nakamura
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Iwashita
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Goto
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009183:Mycotoxins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000199:Actins; D004791:Enzyme Inhibitors; D009183:Mycotoxins; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; C100297:rubratoxins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4