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Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1-induced neurotoxicity
Peter Thornton1, Emmanuel Pinteaux, Stuart M Allan
1Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Abstract:
Matrix metalloproteinases (MMPs) are endopeptidases known to mediate acute neuronal injury, but it is unclear whether these proteases are induced by the primary insult or by inflammation associated with injury. We have reported recently that interleukin-1 (IL-1) induces neurotoxicity by an astrocyte-dependent mechanism. The aim of the present study was to test the hypothesis that MMPs mediate IL-1 neurotoxicity in rat, glial-neuronal cocultures. IL-1beta induced the release of astrocytic MMP-9 in cocultures, whilst an antagonist of MMP-9 inhibited IL-1beta-induced neuronal death. Urokinase plasminogen activator (uPA) was constitutively expressed on neuronal membrane fractions, and amiloride (an antagonist of uPA) or plasminogen activator inhibitor (PAI)-1 significantly reduced IL-1beta-induced neurotoxicity. Thus, neuronal uPA contributes to IL-1 neurotoxicity, and may be responsible for activating MMP-9 released from IL-1-primed astrocytes. In summary, IL-1-induced neurotoxicity is dependent on extracellular protease activity, and these mechanisms may contribute to neuronal cell death in CNS diseases.
Insights
Interleukin-1 (IL-1) causes neuronal death through matrix metalloproteinases (MMPs). Blocking MMP-9 or urokinase plasminogen activator (uPA) protects neurons from IL-1 neurotoxicity, highlighting protease activity in central nervous system diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Matrix metalloproteinases (MMPs) are implicated in acute neuronal injury.
- The role of MMPs in interleukin-1 (IL-1)-induced neurotoxicity remains unclear.
- IL-1 can induce neurotoxicity via an astrocyte-dependent pathway.
Purpose of the Study:
- To investigate if MMPs mediate IL-1 neurotoxicity in rat glial-neuronal cocultures.
- To determine the specific roles of MMP-9 and urokinase plasminogen activator (uPA) in this process.
Main Methods:
- Utilized rat glial-neuronal cocultures.
- Administered IL-1beta to induce neurotoxicity.
- Assessed the effects of MMP-9 antagonists and uPA antagonists (amiloride, plasminogen activator inhibitor-1).
Main Results:
- IL-1beta stimulated the release of astrocytic MMP-9.
- An MMP-9 antagonist significantly reduced IL-1beta-induced neuronal death.
- Neuronal uPA contributed to IL-1 neurotoxicity, as evidenced by amiloride and PAI-1 treatment reducing neuronal death.
- Neuronal uPA may activate MMP-9 released from IL-1-primed astrocytes.
Conclusions:
- IL-1-induced neurotoxicity is dependent on extracellular protease activity.
- MMP-9 and neuronal uPA are key mediators of IL-1 neurotoxicity.
- These protease-dependent mechanisms may contribute to neuronal cell death in central nervous system diseases.
