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 ∼40 μg/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.