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 inflammatory cytokines that include interleukin-1 (IL-1). We report here that the levels of several matrix metalloproteinases (MMPs) are also elevated following a corticectomy trauma injury to the mouse CNS. The delayed upregulation of MMPs compared to that for IL-1 suggests the possibility that inflammatory cytokines regulate MMP production in CNS trauma. To resolve this, we developed a method to isolate and maintain highly enriched human fetal neurons or astrocytes in culture and examined the regulation by cytokines of the activity of a subgroup of MMPs, the gelatinases (MMP-2 and -9). While both neuronal and astrocytic cultures displayed comparable MMP-2 activity, as evidenced by gelatin zymography, levels of MMP-9 were proportionately higher in neurons compared to astrocytes. Of a variety of cytokines and growth factors tested in vitro, only IL-1beta was effective in increasing the neuronal expression of MMP-9. Finally, an IL-1 receptor antagonist attenuated the increase of neuronal MMP-9 in culture and abolished the injury-induced increase of MMP-9 in the mouse brain. These results implicate IL-1beta as a key regulator of neuronal MMP-9 in culture and of the elevation of MMP-9 that occurs following mouse CNS trauma.
Vecil
G G
GG
Department of Clinical Neurosciences University of Calgary, Calgary, Alberta T2N 4N1 Canada.
Larsen
P H
PH
Corley
S M
SM
Herx
L M
LM
Besson
A
A
Goodyer
C G
CG
Yong
V W
VW
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001930:Brain Injuries / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000293:injuries / Q000503:physiopathology; D003470:Culture Media / Q000494:pharmacology; D005260:Female; D005333:Fetus; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012795:Sialoglycoproteins / Q000494:pharmacology
D018501:Antirheumatic Agents; D003470:Culture Media; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9