[STAT mediated thrombin induction of tissue inhibitor of metalloproteinase1 in human mesangial cells].

OBJECTIVE: To depict the role of signal transducers and activators of transcription (STAT) pathway in thrombin induction of tissue inhibitor of matrix metalloproteinase-1 (TIMP1) in human mesangial cells. METHODS: Human mesangial cells were isolated, seeded in RPMI1640, and stimulated with thrombin (0.5, 1.5, and 4.5 U/ml). Northern blot and electrophoretic mobility shift assay (EMSA) were employed to determine the levels of TIMP1 mRNA and STAT-DNA binding activity in the cells, respectively. In order to confirm the role of STAT in this cell event, STAT 1 and STAT 3 antisense oligonucleotides were employed to suppress their intra-cellular activity. CONCLUSION: Cultured human mesangial cells expressed basal TIMP1 mRNA, and thrombin promoted TIMP1 gene transcription in dose-dependent manner. Hirudin, a specific inhibitor of thrombin, blocked thrombin-induced TIMP1 gene expression. Thrombin promoted STAT DNA binding activity in a manner parallel to TIMP1 mRNA expression, which was inhibited by its inhibitor, hirudin again. STAT1 and STAT3 antisense oligonucleotides inhibited both STAT DNA binding activity and TIMP1 mRNA expression in mesangial cells. CONCLUSION: STAT mediates the thrombin-induced expression of TIMP1 gene in cultured human mesangial cells.