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

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 E₂ (PGE₂) production in brain astrocytes. However, the relationship between BK-induced MMP-9 expression and COX-2-derived PGE₂ release in brain astrocytes remains unclear. Methods: Herein we used rat brain astrocytes (RBA) to investigate the role of the COX-2/PGE₂ 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/PGE₂-dependent pathway. Results: Our results show activation of native COX-2 by BK led to PGE₂ production and release. Subsequently, PGE₂ induced MMP-9 expression via PGE₂ 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/PGE₂-mediated c-Src/Jak2/ERK cascades in brain astrocytes. Dm4iGs5nWD8FkGrYCfJL2M Video Abstract [ABSTRACT FROM AUTHOR]