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Evidence Implicating Matrix Metalloproteinases in the Mechanism Underlying Accumulation of IL-1beta and Neuronal Apoptosis in the Neocortex of HIV/gp120-Exposed Rats.

Authors: Russo, R  Siviglia, E  Gliozzi, M  Amantea, D  Paoletti, A  Berliocchi, L  Bagetta, G  Corasaniti, MT 
Citation: Russo R, etal., Int Rev Neurobiol. 2007;82C:407-421.
Pubmed: (View Article at PubMed) PMID:17678975
DOI: Full-text: DOI:10.1016/S0074-7742(07)82023-X

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.


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RGD Object Information
RGD ID: 1626641
Created: 2007-08-14
Species: All species
Last Modified: 2007-08-14
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.