Role of Protein Kinase A in Collagenase-1 Gene Regulation by Prostaglandin E1: Studies in a Rabbit Synoviocyte Cell Line, HIG-82

The Journal of Immunology

Rosenthal

Tolani

et al. 2003

We examined the regulation of matrix metalloproteinase (MMP) production by mitogen-activated protein kinases and cyclooxygenases (COXs) in fibroblast-like synoviocytes (FLSCs). IL-1β and TNF-α stimulated FLSC extracellular signal-regulated kinase (ERK) activation as well as MMP-1 and -13 release. Pharmacologic inhibitors of ERK inhibited MMP-1, but not MMP-13 expression. Whereas millimolar salicylates inhibited both ERK and MMP-1, nonsalicylate COX and selective COX-2 inhibitors enhanced stimulated MMP-1 release. Addition of exogenous PGE1 or PGE2 inhibited MMP-1, reversed the effects of COX inhibitors, and inhibited ERK activation, suggesting that COX-2 activity tonically inhibits MMP-1 production via ERK inhibition by E PGs. Exposure of FLSCs to nonselective COX and selective COX-2 inhibitors in the absence of stimulation resulted in up-regulation of MMP-1 expression in an ERK-dependent manner. Moreover, COX inhibition sufficient to reduce PGE levels increased ERK activity. Our data indicate that: 1) ERK activation mediates MMP-1 but not MMP-13 release from FLSCs, 2) COX-2-derived E PGs inhibit MMP-1 release from FLSCs via inhibition of ERK, and 3) COX inhibitors, by attenuating PGE inhibition of ERK, enhance the release of MMP-1 by FLSC.

Section: E-series Pgs Inhibit Both Extracellular Mmp-1 Expression Andsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 52%

Cyclooxygenase-2-Derived E Prostaglandins Down-Regulate Matrix Metalloproteinase-1 Expression in Fibroblast-Like Synoviocytes via Inhibition of Extracellular Signal-Regulated Kinase Activation

The Journal of Immunology

Rosenthal

Tolani

et al. 2003

“…MMP-1 responses in other cell types (15,20,34,35,40,53,54), we asked whether they would affect AGS cells. Preincubation of AGS cells with PGE 1 or PGE 2 enhanced both Erk activation and MMP-1 secretion in response to EGF (Fig.…”

Section: Pges Regulate Erk Activation and Mmp-1 But Not Mmp-13 Secretmentioning

confidence: 99%

Matrix Metalloproteinase Secretion by Gastric Epithelial Cells Is Regulated by E Prostaglandins and MAPKs

Journal of Biological Chemistry

Marjanović

Kim

et al. 2005

Because matrix metalloproteinases (MMPs) play roles in inflammatory tissue injury, we asked whether MMP secretion by gastric epithelial cells may contribute to gastric injury in response to signals involved in Helicobacter pylori-induced inflammation and/or cyclooxygenase inhibition. Tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, and epidermal growth factor (EGF) stimulated gastric cell MMP-1 secretion, indicating that MMP-1 secretion occurs in inflammatory as well as noninflammatory situations. MMP-1 secretion required activation of the MAPK Erk and subsequent protein synthesis but was down-regulated by the alternate MAPK, p38. In contrast, secretion of MMP-13 was stimulated by TNF-␣/IL-1␤ but not EGF and was Erk-independent and mediated by p38. MMP-13 secretion was more rapid (peak, 6 h) than MMP-1 (peak >30 h) and only partly depended on protein synthesis, suggesting initial release of a pre-existing MMP-13 pool. Therefore, MMP-1 and MMP-13 secretion are differentially regulated by MAPKs. MMP-1 secretion was regulated by E prostaglandins (PGEs) in an Erk-dependent manner. PGEs enhanced Erk activation and MMP-1 secretion in response to EGF but inhibited Erk and MMP-1 when TNF-␣ and IL-1␤ were the stimuli, indicating that the effects of PGEs on gastric cell responses are context-dependent. These data show that secretion of MMPs is differentially regulated by MAPKs and suggest mechanisms through which H. pylori infection and/or cyclooxygenase inhibition may induce epithelial cell signaling to contribute to gastric ulcerogenesis.

“…Studies by Zurier and colleagues (20,21) indicate that PGEs can reduce inflammation in animal models of arthritis and nephritis. In rabbit SF, PGE 2 inhibits secretion of MMP-1, again via effects on ERK (3,22,23). Thus, PGEs may actually be complex mediators of inflammation, with both inflammatory and anti-inflammatory effects.…”

mentioning

confidence: 99%

Resolution of Inflammation: Prostaglandin E2 Dissociates Nuclear Trafficking of Individual NF-κB Subunits (p65, p50) in Stimulated Rheumatoid Synovial Fibroblasts

Gomez

The Journal of Immunology

Attur

et al. 2005

121

NF-κB transcription factors regulate inflammatory responses to cytokines such as IL-1β and TNF-α. We tested whether PGE2 regulated nuclear localization of individual NF-κB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1β/TNF-α stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-κB activation measured by luciferase reporter assay. PGE2 (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-κB activation. In contrast, depletion of endogenous PGE2 by ibuprofen (100 μM) and celecoxib (5 μM) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-κB DNA binding sites. PGE2 also blocked IL-1β/TNF-α-stimulated ERK activation, and the ERK inhibitor, PD98059, mimicked PGE2 in blocking p65, but enhancing p50 nuclear translocation, suggesting that the effects of PGE2 on p65 and p50 are mediated via effects on ERK. PGE2 also enhanced the expression of IκBα in an ERK-independent manner, suggesting that PGE2 inhibits NF-κB activation by both ERK-dependent and -independent mechanisms. Our data indicate that PGE2 may act to attenuate cytokine-induced inflammatory responses in RA synovial fibroblasts via regulation of the localization of specific NF-κB family dimers.