Identification of the interleukin-6/oncostation M response element in the rat tissue inhibitor of metalloproteinases-1 (TIMP-1)Promoter

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Abstract
The rat tissue inhibitor of metalloproteinases 1 (TIMP-1) gene is expressed in rat hepatocytes, and this expression Is up-regulated by interieukln 6 (IL-6). We report here the cloning of the 5′ flanking region of the rat TIMP-1 gene and identification of an IL-6/oncostatln M (OSM) response element at −64 to −36 which functions In hepatic cells. Within this element we have identified two functional binding sites for transcription factors AP-1 (activatory proteln-1) and STAT (signal transducer and activator of transcription). IL-6/OSM stimulation Induces binding of a protein, identified as STAT3, to the IL-6/0SM response element, while binding of the AP-1 protein was constitutive. Binding sites for both AP-1 and STAT3 are necessary for full responsiveness of the TIMP-1 promoter to IL-6/OSM, as shown by deletion and mutation analysis. Furthermore, the entire IL-6/OSM response element conferred responsiveness onto a heterologous promoter, whereas this has not been observed when AP-1 and STAT elements were separately tested.

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