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In the context of disease, TIMP\u20101 has emerged as an important multifunctional protein capable of regulating inflammation. We previously reported differential TIMP\u20101 expression in acute versus chronic activation of astrocytes. This study investigates possible mechanisms underlying TIMP\u20101 downregulation in chronic neuroinflammation. We used interleukin (IL)\u20101\u03b2 as a model pro\u2010inflammatory stimulus and measured TIMP\u20101 binding to extracellular matrix, cell death, receptor downregulation, TIMP\u20101 mRNA stability and transcriptional regulation in activated astrocytes. TIMP\u20101 remained localized to the cell body or was secreted into the cell supernatant. DNA fragmentation ELISA and MTT assay showed that prolonged IL\u20101\u03b2 activation of astrocytes induced significant astrocyte death. In acute and chronic IL\u20101\u03b2\u2010activated astrocytes, IL\u20101 receptor levels were not significantly different. TIMP\u20101 mRNA stability was measured in astrocytes and U87 astroglioma cells by real\u2010time PCR, and TIMP\u20101 promoter activation was studied using TIMP\u20101\u2010luciferase reporter constructs in transfected astrocytes. Our results indicated that TIMP\u20101 expression is regulated through multiple mechanisms. Transcriptional control and loss of mRNA stabilization are, however, the most likely primary contributors to chronic downregulation of TIMP\u20101. These data are important for unraveling the mechanisms underlying astrocyte responses during chronic neuroinflammation and have broader implications in other inflammatory diseases that involve MMP\/TIMP imbalance. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.20823","type":"journal-article","created":{"date-parts":[[2006,3,22]],"date-time":"2006-03-22T21:22:37Z","timestamp":1143062557000},"page":"1281-1292","source":"Crossref","is-referenced-by-count":45,"title":["Potential mechanisms for astrocyte\u2010TIMP\u20101 downregulation in chronic inflammatory diseases"],"prefix":"10.1002","volume":"83","author":[{"given":"Jessica","family":"Gardner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Borgmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muralidhar 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