A representative metalloprotease induces PGE2 synthesis in fibroblast-like synoviocytes via the NF-κB/COX-2 pathway with amplification by IL-1β and the EP4 receptor

Abstract

Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. This study showed that the snake venom metalloprotease (SVMP) BaP1 activates FLSs to produce PGE 2 by a mechanism dependent on COX-2, mPGES-1 and iPLA 2 s. BaP1 also induces IL-1β release, which up-regulates the production of PGE 2 at a late stage of the stimulation. Expression of COX-2 and mPGES-1 are induced by BaP1 via activation of NF-κB pathway. While NF-κB p50 and p65 subunits are involved in up-regulation of COX-2 expression, only p65 is involved in BaP1induced mPGES-1 expression. In addition, BaP1 up-regulates EP4 receptor expression. Engagement of this receptor by PGE 2 triggers a positive feedback loop for its production by up-regulating expression of key components of the PGE 2 biosynthetic cascade (COX-2, mPGES-1 and the EP4 receptor), thus contributing to amplification of BaP1-induced effects in FLSs. These data highlight the importance of FLS as a target for metalloproteases in joint inflammation and provide new insights into the roles of MMPs in inflammatory joint diseases. Moreover, our results may give insights into the importance of the catalytic domain, of MMPs for the inflammatory activity of these enzymes.

A Metalloproteinase Induces an Inflammatory Response in Preadipocytes with the Activation of COX Signalling Pathways and Participation of Endogenous Phospholipases A2

“…Our results, which showed that the pharmacological inhibition of cytosolic PLA 2 s or group-IIA-secreted PLA 2 s markedly reduced the BmooMPα-I-induced release of PGE 2 , indicated that both cytosolic and group-IIA-secreted PLA 2 s are important players in the generation of PGE 2 following BmooMPα-I stimulus. These findings are evidence of a link between metalloproteinases and PLA 2 s, by which the venom metalloproteinase stimulates preadipocytes to produce PGE 2 ; they are in accordance with previous studies demonstrating a link between metalloproteinases and PLA 2 for the production of PGE 2 by fibroblast-like synoviocytes [72]. On the other hand, a negative regulation of a cardiac sPLA 2 by MMP-2 in a proinflammatory setting has been previously reported, since in MMP-2 deficient mice the production and release of a unique sPLA 2 was increased in cardiomyocytes [84,85]; thus, MMPs may act as modulators of distinct members of the PLA 2 family and may regulate inflammation signaling, both when expressed in excess and when underexpressed.…”

“…In addition, our results showing that the inhibition of the BmooMPα-I catalytic domain abolished PGE 2 release and COX-2 protein expression indicate that the catalytic activity of BmooMPα-I is essential for the activation of the biosynthetic pathway for the production of prostanoids in preadipocytes. Considering that the catalytic domain of metalloproteinases was demonstrated to be responsible for the degradation of ECM components and for the processing of non-matrix proteins, such as cytokines, chemokines, and receptors [11,72], our findings provide insight into the role of the catalytic domain of MMPs in the release of lipid mediators triggered by this class of enzymes.…”

“…The concentrations of BmooMPα-I able to induce release of these prostaglandins were comparable to those described for relevant MMPs, such as MMP-2, in the plasma of obese patients [6]; therefore, it is plausible to suggest that PGE 2 and PGI 2 can mediate the inflammatory actions of metalloproteinases in the adipose tissue and exert paracrine actions in structures adjacent to this tissue, contributing to the development of distinct inflammatory conditions, such as arthropathies [18,23]. Although the ability of MMP-1 and MMP-3 to release PGE 2 from isolated macrophages and of an SVMP, BaP1, to release this mediator by fibroblast-like synoviocytes [61,72] has previously been reported, to our knowledge this is the first report providing evidence of a metalloproteinase inducing the production of PGE 2 and PGI 2 by adipose tissue cells.…”

Research Progress of Therapeutic Enzymes and Their Derivatives: Based on Herbal Medicinal Products in Rheumatoid Arthritis

“…Among these mediators, the inflammatory factors such as IL-1β and TNF-α activate and accelerate the generation of matrix metalloproteases (MMPs), which will significantly increase the total activities of MMPs indirectly. The enzyme family can irreversibly promote the degradation of extracellular matrix (ECM) ingredients, including the collagen and fibronectin in the place of articular cartilage and bone ( Viana et al, 2020 ). The major components of cartilage are type II collagen and proteoglycans, while type I collagen primarily constitutes the bone.…”

A Representative GIIA Phospholipase A2 Activates Preadipocytes to Produce Inflammatory Mediators Implicated in Obesity Development

“…PGE 2 exerts its effects through activation of four subtypes of G protein-coupled receptors, named EP1, EP2, EP3 and EP4, and these receptors are able to regulate PGE 2 biosynthesis [34,37,41]. It is known that the activation of the EP4 receptor by PGE 2 may lead to the increased expression of key enzymes of biosynthesis cascade of this prostaglandin, such as COX-2 and mPGES-1 [8,41,42]. Therefore, we investigated whether PGE 2 biosynthesis, induced by MT-III, was dependent on the activation of these receptors.…”