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

Abstract

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.

Calycosin alleviatesH2O2‐induced astrocyte injury by restricting oxidative stress through the Akt/Nrf2/HO‐1 signaling pathway

“…The previous studies have reported that astrocytes can be used as an in vitro model to evaluate the inflammatory processes of the CNS disorders. 8,36,37 Because, astrocytes are the most abundant glial cell type in the CNS and outnumber neurons by over fivefold. 38 They 39 The pathogenesis of brain dysfunction is multifactorial and often associated with astrocyte injury.…”

The Bradykinin System Contributes to the Regulation of Prostaglandin-Endoperoxide Synthase 2 Expression in Human Amnion Fibroblasts: Implications for Term and Preterm Birth

“…The bradykinin system is implicated in inflammatory responses through induction of not only vasodilation and fluid expansion but also the production of inflammatory mediators such as cytokines and prostaglandins ( 7 – 9 , 14 , 40 ). The bradykinin system has been implicated in a number of inflammatory events of female reproduction, including embryo implantation and ovulation ( 41 – 43 ).…”

“…Of note, excessive accumulation of DABK can even evolve into a bradykinin storm resulting in severe inflammatory responses when its metabolism is left unchecked ( 9 – 11 ), suggesting a crucial role of bradykinin peptides in inflammation. It has been shown that BK and DABK participate in inflammation responses not only by increasing vasodilation and vascular permeability but also by stimulating the production of proinflammatory factors including cytokines and prostaglandins ( 1 , 12 – 14 ). In terms of prostaglandin synthesis, bradykinin peptides induce the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis in various cell types ( 14 – 19 ).…”

A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming

“…Furthermore, COX-2 is a rate-limiting enzyme that mediates the production of prostaglandin E2 (PGE2) from arachidonic acid (AA). Subsequently, PGE2 activates a JAK2/STAT3 pathway to elevate the expression of metallopeptidase 9 (MMP9) (Kawahara et al 2015 ; Lee et al 2020 ). On the other hand, our intracellular profiles (Fig.…”