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

• Published in: International journal of radiation oncology, biology, physics Vol. 46; no. 3; pp. 407 - 421
• Main Authors: Russo, Rossella, Siviglia, Elisa, Gliozzi, Micaela, Amantea, Diana, Paoletti, Annamaria, Berliocchi, Laura, Bagetta, G, Corasaniti, M Tiziana
• Format: Journal Article
• Language: English
• Published: 2007
• Subjects: Human immunodeficiency virus 1
• ISSN: 0360-3016
• 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-1 beta (IL-1 beta ) is one of the main mediators of inflammation, and IL-1 beta expression in the brain is rapidly upregulated in response to acute and chronic insults. IL-1 beta is synthesized as biologically inactive precursor (pro-IL-1 beta ), 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-1 beta processing have recently been suggested. Here we report that matrix metalloproteinases (MMPs) participate in the maturation process (cleavage and activation) of IL-1 beta 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-1 beta immunoreactivity and the neuronal apoptosis induced by gp120. Taken together, these findings point to a critical role for MMPs in IL-1 beta increase and consequent neurotoxicity triggered by gp120 in the neocortex of rat and suggest new links between IL-1 beta processing and MMP activation during the neuroinflammatory process.