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AUF‐1 mediates inhibition by nitric oxide of lipopolysaccharide‐induced matrix metalloproteinase‐9 expression in cultured astrocytes
Author(s) -
Liu Wenlan,
Rosenberg Gary A.,
Liu Ke Jian
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20895
Subject(s) - lipopolysaccharide , nitric oxide , matrix metalloproteinase , matrix metalloproteinase 9 , chemistry , pharmacology , matrix (chemical analysis) , microbiology and biotechnology , medicine , endocrinology , biochemistry , biology , chromatography , organic chemistry
Neuroinflammatory diseases are associated with increased production of matrix metalloproteinase‐9 (MMP‐9) and excessive generation of nitric oxide (NO). NO hasbeen reported to have variable effects on MMP‐9 gene expression and activation in various cell types. Inthe present study, we investigated the effect of NOon MMP‐9 expression in primary cortical astrocytes. Zymography and real‐time PCR showed that lipopolysaccharide (LPS) dramatically increased latent MMP‐9 gelatinolytic activity and MMP‐9 mRNA expression. By using the NO donor DETA NONOate, we observed a dose‐dependent inhibition of MMP‐9 induction by LPS. Active forms of MMP‐9 were not found by zymography after NO treatment. The MEK1/2 inhibitor U0126 completely inhibited LPS‐induced MMP‐9, which was partially inhibited by the p38 MAPK inhibitor SB203580. NO had no effect on LPS‐stimulated ERK1/2 and p38 MAPK activation, suggesting that the inhibitory action of NO occurs downstream of MAPK cascades. Real‐time PCR analysis showed that NO accelerated the degradation of MMP‐9 mRNA after LPS induction. Western blotting and pull‐down assay demonstrated that NO increased AUF‐1 expression as well as its specific binding to the MMP‐9 gene 3′‐untranslated region. Knockdown of AUF‐1 with siRNA partially reversed the inhibitory action of NO on LPS‐stimulated MMP‐9 induction. We conclude that NO does not activate MMP‐9 in astrocyte cultures but reduces LPS‐induced MMP‐9 expression via accelerating MMP‐9 mRNA degradation, which is partially mediated by AUF‐1. Our results suggest that elevated NO concentrations may suppress MMP‐9 and restrict the inflammatory response in neurodegenerative diseases. © 2006 Wiley‐Liss, Inc.