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Background  The matrix metalloproteinase-9 (MMP-9) is up-regulated by several proinflammatory mediators in the central nervous system (CNS) diseases. Increasing reports show that MMP-9 expression is an inflammatory biomarker of several CNS disorders, including the CNS inflammation and neurodegeneration. Bradykinin (BK) is a common proinflammatory mediator and elevated in several brain injury and inflammatory disorders. The raised BK may be detrimental effects on the CNS that may aggravate brain inflammation through MMP-9 up-regulation or cyclooxygenase-2 (COX-2)-derived prostaglandin E 2  (PGE 2 ) production in brain astrocytes. However, the relationship between BK-induced MMP-9 expression and COX-2-derived PGE 2  release in brain astrocytes remains unclear.    Methods  Herein we used rat brain astrocytes (RBA) to investigate the role of the COX-2/PGE 2  system in BK-induced MMP-9 expression. We used zymographic, RT-PCR, EIA, and Western blotting analyses to confirm that BK induces MMP-9 expression via a COX-2/PGE 2 -dependent pathway.    Results  Our results show activation of native COX-2 by BK led to PGE 2  production and release. Subsequently, PGE 2  induced MMP-9 expression via PGE 2  receptor (EP)-mediated c-Src, Jak2, ERK1/2, and then activated signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, up-regulation of MMP-9 by BK via the pathway may promote astrocytic migration.    Conclusion  These results demonstrated that a novel autocrine pathway for BK-induced MMP-9 protein expression is mediated through activation of STAT3 by native COX-2/PGE 2 -mediated c-Src/Jak2/ERK cascades in brain astrocytes.Video Abstract

The COX-2-derived PGE2 autocrine contributes to bradykinin-induced matrix metalloproteinase-9 expression and astrocytic migration via STAT3 signaling