Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1-induced neurotoxicity.
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.
Thornton
Peter
P
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Pinteaux
Emmanuel
E
Allan
Stuart M
SM
Rothwell
Nancy J
NJ
D000584:Amiloride / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000633:toxicity*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009457:Neuroglia / Q000737:chemistry / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D017395:Plasminogen Activator Inhibitor 1; D026941:Sodium Channel Blockers; D000584:Amiloride; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9