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

Tsong-Hai Lee,Pei-Shan Liu,Jiun-Liang Chen,Su-Jane Wang,Ming-Ming Tsai,Hsi-Lung Hsieh

doi:10.1186/s12964-020-00680-0

Abstract

BackgroundThe 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.MethodsHerein 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.ResultsOur 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.ConclusionThese 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.9AsGp9CBXvHHi3gF-G6FRAVideo

Highlights

The matrix metalloproteinase-9 (MMP-9) is up-regulated by several proinflammatory mediators in the central nervous system (CNS) diseases
We further demonstrated whether BK induces Matrix metalloproteinases (MMPs)-9 expression via cyclooxy‐ genase-2 (COX-2)/Prostaglandin E2 (PGE2)-dependent activation of Jak2/ signal transducer and activator of transcription 3 (STAT3) pathways, rat brain astrocytes (RBA) cells were directly treated with PGE2
Pretreatment with PP1 attenuated PGE2-stimulated Jak2 and STAT3β phosphorylation (Fig. 6d), indicating that c-Src may be an upstream regulator of Jak2/STAT3β cascade in RBA cells. These results suggested that COX-2/PGE2 systemdependent activation of Jak2/STAT3β cascade is a novel and critical pathway for BK-induced MMP-9 expression in brain astrocytes

Summary

Introduction

The matrix metalloproteinase-9 (MMP-9) is up-regulated by several proinflammatory mediators in the central nervous system (CNS) diseases. The raised BK may be detrimental effects on the CNS that may aggravate brain inflammation through MMP-9 up-regulation or cyclooxy‐ genase-2 (COX-2)-derived prostaglandin E2 (PGE2) production in brain astrocytes. The relationship between BK-induced MMP-9 expression and COX-2-derived PGE2 release in brain astrocytes remains unclear. Up-regulation of COX-2 leads to increased production of PGs which may be associated with the central nervous system (CNS) inflammation and neurodegenerative disorders [6]. We have demonstrated that several proinflammatory mediators like bradykinin (BK) can induce COX-2 expression and PGE2 production in brain astrocytes [7]. The COX-2/PGE2 system may exert as a critical pathological mediator in brain inflammatory diseases

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