Publications (2)2.35 Total impact
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Article: Evidence implicating matrix metalloproteinases in the mechanism underlying accumulation of IL-1beta and neuronal apoptosis in the neocortex of HIV/gp120-exposed rats.
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ABSTRACT: Neuroinflammation is often associated with neurodegenerative diseases, including multiple sclerosis (MS), stroke, Alzheimer's disease, and HIV-1-associated dementia (HAD). The proinflammatory cytokine interleukin-1beta (IL-1beta) is one of the main mediators of inflammation, and IL-1beta expression in the brain is rapidly upregulated in response to acute and chronic insults. IL-1beta is synthesized as biologically inactive precursor (pro-IL-1beta), which is classically processed by caspase-1 [also known as interleukin-converting enzyme (ICE)] into the active, mature cytokine. However, caspase-1/ICE-independent mechanisms of IL-1beta processing have recently been suggested. Here we report that matrix metalloproteinases (MMPs) participate in the maturation process (cleavage and activation) of IL-1beta in an in vivo model of HIV-associated neurodegeneration based on the intracerebroventricular injection of the HIV-1 envelope glycoprotein gp120. We show that, following gp120 exposure, MMP-9 and MMP-2, but not caspase-1/ICE, are rapidly induced. Pharmacological manipulation of MMPs activity, using the broad spectrum MMPs inhibitor GM6001, reduces the increase in IL-1beta immunoreactivity and the neuronal apoptosis induced by gp120. Taken together, these findings point to a critical role for MMPs in IL-1beta increase and consequent neurotoxicity triggered by gp120 in the neocortex of rat and suggest new links between IL-1beta processing and MMP activation during the neuroinflammatory process.International Review of Neurobiology 02/2007; 82:407-21. · 2.35 Impact Factor -
Article: Evidence Implicating Matrix Metalloproteinases in the Mechanism Underlying Accumulation of IL‐1β and Neuronal Apoptosis in the Neocortex of HIV/gp120‐Exposed Rats
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ABSTRACT: Neuroinflammation is often associated with neurodegenerative diseases, including multiple sclerosis (MS), stroke, Alzheimer's disease, and HIV‐1‐associated dementia (HAD). The proinflammatory cytokine interleukin‐1β (IL‐1β) is one of the main mediators of inflammation, and IL‐1β expression in the brain is rapidly upregulated in response to acute and chronic insults. IL‐1β is synthesized as biologically inactive precursor (pro‐IL‐1β), which is classically processed by caspase‐1 [also known as interleukin‐converting enzyme (ICE)] into the active, mature cytokine. However, caspase‐1/ICE‐independent mechanisms of IL‐1β processing have recently been suggested. Here we report that matrix metalloproteinases (MMPs) participate in the maturation process (cleavage and activation) of IL‐1β in an in vivo model of HIV‐associated neurodegeneration based on the intracerebroventricular injection of the HIV‐1 envelope glycoprotein gp120. We show that, following gp120 exposure, MMP‐9 and MMP‐2, but not caspase‐1/ICE, are rapidly induced. Pharmacological manipulation of MMPs activity, using the broad spectrum MMPs inhibitor GM6001, reduces the increase in IL‐1β immunoreactivity and the neuronal apoptosis induced by gp120. Taken together, these findings point to a critical role for MMPs in IL‐1β increase and consequent neurotoxicity triggered by gp120 in the neocortex of rat and suggest new links between IL‐1β processing and MMP activation during the neuroinflammatory process.International Review of Neurobiology.
