Regulation of tissue inhibitor of metalloproteinase-1 by astrocytes: Links to HIV-1 dementia
| Autor: | Li Wu, Yuri Persidsky, Kathleen Borgmann, Spring Holter, Anuja Ghorpade, Christine Labenz-Zink, Howard E. Gendelman, Raisa Persidsky, Radhika Suryadevara |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
AIDS Dementia Complex Down-Regulation Inflammation Biology Matrix metalloproteinase Article Monocytes Cellular and Molecular Neuroscience Fetus Internal medicine Glial Fibrillary Acidic Protein medicine Humans Gliosis RNA Messenger Cells Cultured Tissue Inhibitor of Metalloproteinase-1 Neurotoxicity Brain Tissue inhibitor of metalloproteinase medicine.disease Up-Regulation Astrogliosis medicine.anatomical_structure Endocrinology Neurology Astrocytes Immunology HIV-1 Encephalitis Matrix Metalloproteinase 2 Neuroglia Matrix Metalloproteinase 1 medicine.symptom Interleukin-1 Astrocyte |
| Zdroj: | Glia. 44:47-56 |
| ISSN: | 1098-1136 0894-1491 |
| DOI: | 10.1002/glia.10266 |
| Popis: | The neuropathogenesis of HIV-1-associated dementia (HAD) revolves around the secretion of toxic molecules from infected and immune-competent mononuclear phagocytes. Astrocyte activation occurs in parallel but limited insights are available for its role in neurotoxicity and cognitive dysfunction. One means in which astrocytes may affect disease is through their production of tissue inhibitors of metalloproteinases (TIMPs). TIMPs are regulators of matrix metalloproteinases, enzymes that affect blood-brain barrier integrity through altering the extracellular matrix. We hypothesized that in response to injury and inflammation in HAD, astrocytes regulate the production of TIMP-1, the inducible type of TIMP that is important in inflammation. To address astrocyte-mediated TIMP-1 regulation in HAD, we evaluated the responses of primary human to IL-1beta and HIV-1. TIMP-1 levels in plasma, CSF, and brain tissue of control, HIV-1 infected patients without cognitive impairment, and HAD patients were also studied. Our data show that an upregulation of TIMP-1 results from astrocytes acutely activated with IL-1beta. In contrast, CSF and brain tissue samples from HAD patients showed reduced TIMP-1 levels compared to seronegative controls. MMP-2 levels in brains showed the opposite. Consistent with this, prolonged activation of astrocytes led to a reduction in TIMP-1 and MMP-2, but a sustained elevation in MMP-1. Our data suggest that in diseased brain tissue, the ability of astrocytes to counteract the destructive effects of MMP through expression of TIMP-1 is diminished by chronic activation. Our studies reveal new opportunities for repair-based therapeutic strategies in HAD. |
| Databáze: | OpenAIRE |
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