Interleukin-1 is a key regulator of matrix metalloproteinase-9 expression in human neurons in culture and following mouse brain trauma in vivo

An acute trauma to the CNS rapidly results in the upregulation of inflammat ory cytokines that include interleukin-1 (IL-1). We report here that the le vels of several matrix metalloproteinases (MMPs) are also elevated followin g a corticectomy trauma injury to the mouse CNS. The delayed upregulation o f MMPs compared to that for IL-1 suggests the possibility that inflammatory cytokines regulate MMP production in CNS trauma. To resolve this, we devel oped a method to isolate and maintain highly enriched human fetal neurons o r astrocytes in culture and examined the regulation by cytokines of the act ivity of a subgroup of MMPs, the gelatinases (MMP-2 and -9). While both neu ronal and astrocytic cultures displayed comparable MMP-2 activity, as evide nced by gelatin zymography, levels of MMP-9 were proportionately higher in neurons compared to astrocytes, Of a variety of cytokines and growth factor s tested in vitro, only IL-1 beta was effective in increasing the neuronal expression of MMP-9. Finally, an IL-1 receptor antagonist attenuated the in crease of neuronal MMP-9 in culture and abolished the injury-induced increa se of MMP-9 in the mouse brain. These results implicate IL-1 beta as a key regulator of neuronal MMP-9 in culture and of the elevation of MMP-9 that o ccurs following mouse CNS trauma. (C) 2000 Wiley-Liss, Inc.