Potential mechanisms for astrocyte-TIMP-1 downregulation in chronic inflammatory diseases

Jessica Gardner, Kathleen Ruth Borgmann, Muralidhar S. Deshpande, Alok Dhar, Li Wu, Raisa Persidsky, Anuja Ghorpade

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

The pathogenesis of many neurodegenerative disorders, including human immunodeficiency virus (HIV)-1 associated dementia, is exacerbated by an imbalance between matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). In the context of disease, TIMP-1 has emerged as an important multifunctional protein capable of regulating inflammation. We previously reported differential TIMP-1 expression in acute versus chronic activation of astrocytes. This study investigates possible mechanisms underlying TIMP-1 downregulation in chronic neuroinflammation. We used interleukin (IL)-1β as a model pro-inflammatory stimulus and measured TIMP-1 binding to extracellular matrix, cell death, receptor downregulation, TIMP-1 mRNA stability and transcriptional regulation in activated astrocytes. TIMP-1 remained localized to the cell body or was secreted into the cell supernatant. DNA fragmentation ELISA and MTT assay showed that prolonged IL-1β activation of astrocytes induced significant astrocyte death. In acute and chronic IL-1β-activated astrocytes, IL-1 receptor levels were not significantly different. TIMP-1 mRNA stability was measured in astrocytes and U87 astroglioma cells by real-time PCR, and TIMP-1 promoter activation was studied using TIMP-1-luciferase reporter constructs in transfected astrocytes. Our results indicated that TIMP-1 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-1. 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.

Original languageEnglish
Pages (from-to)1281-1292
Number of pages12
JournalJournal of Neuroscience Research
Volume83
Issue number7
DOIs
StatePublished - 15 May 2006

Keywords

  • HIV-1
  • IL-1β
  • Neurodegenerative disorders
  • TIMP-1

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