Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-κB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis

Abstract

High concentration of epidermal growth factor (EGF) is found in the synovial fluid of rheumatoid arthritis (RA) that might imply the involvement of EGF in the pathogenesis of arthritic diseases. In order to investigate if EGF is involved in the regulation of cyclooxygenase-2 (COX-2) and the prostaglandin E(2) (PGE(2)) production in fibroblast like synoviocytes (FLS) from patients with RA. The levels of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) were evaluated using RT-PCR and Western blot analysis. Electrophoretic mobility shift assay (EMSA) was performed to investigate EGF mediated DNA binding activity of nuclear factor-kappaB (NF-kappaB). PGE(2) levels were analyzed by ELISA. EGF enhanced both COX-2 protein and mRNA expressions. mPGES-1 mRNA level was also increased by EGF treatment. EGF also stimulated ERK1/2 MAPK activity and the inhibition of ERK1/2 by PD098059 (ERK1/2 specific inhibitor) resulted in the suppression of EGF-induced COX-2 expression. The DNA binding activity of NF-kappaB was remarkably increased by EGF treatment and the pretreatment of PD098059 abolished EGF-stimulated NF-kappaB activity. We also observed that the level of PGE(2) was significantly elevated with the treatment of EGF in FLS, and the pretreatment of PD098059 abolished this stimulating effect. These results suggest that EGF is involved in the inflammatory process of RA by stimulating COX-2 expression and PGE(2) production. And EGF enhanced PGE(2) production appears to be mediated via ERK1/2 MAPK and NF-kappaB pathway in FLS.

Aryl Hydrocarbon Receptor Antagonism Attenuates Growth Factor Expression, Proliferation, and Migration in Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

“…GNF351 is a complete antagonist that inhibits both AHR-mediated, DRE-dependent activity induced by agonists as well as selective AHR modulator-mediated, DREindependent AHR signaling (Nah et al, 2010;Zhao et al, 2010;Smith et al, 2011). GNF351 has been shown to inhibit nuclear translocation of the AHR in an immortalized FLS line (K4IM), thus inhibiting DRE-mediated transcription of inflammatory cytokines such as IL1B and IL6 .…”

“…FLS hyperplasia serves as a key link between immune cell activity and joint destruction and thus can be considered a hallmark event in RA progression (Qu et al, 1994a). It has been shown that FLS play a constitutive role in the secretion of a number of growth factors, including vascular endothelial growth factors (VEGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) (Lee et al, 2001;Malemud, 2007;Nah et al, 2010). In turn, growth factor secretion has been shown to activate FLS, leading to hyperplasia and increased angiogenesis, which results in augmented RA severity and progression (Koch, 2000).…”

EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity

“…The connection between EGF/EGFR and mPGES-1 in promotion of tumorigenicty in epithelial cells, so far largely surmised from work on non-tumor cells (that is, synoviocytes) (Nah et al, 2010), is clearly demonstrated here by two lines of evidence. First, the clonogenic assay showed that abrogation of the mPGES-1 gene in tumor epithelial cells (HT-29) markedly reduced the EGF tumorigenic potential.…”

“…In this study, we focused on mPGES-1 examining its induction in cultured epithelial tumor cells (HT-29, colon, A431, squamous cell, and A549, lung adenocarcinoma) following stimulation by EGF. Although a number of reports have described the relationship between mPGES-1 overexpression and tumor growth, the evidence that the enhanced malignancy is linked to a transduction loop between the prostanoid and the EGF system is fragmentary (Hanaka et al, 2009;Nah et al, 2010;Wang and Dubois, 2010;Lu et al, 2012). Our aim was to demonstrate that the mPGES-1/PGE2 and the EGF axis provide a cohesive program for malignancy in epithelium.…”

Niemann-Pick Type C2 Deficiency in Human Fibroblasts Confers Robust and Selective Activation of Prostaglandin E2 Biosynthesis

“…RTK/GFR 3 ERK1/2 signaling is one of the major driving forces for PGE2 production where it up-regulates the expression and activity of the components in the cPLA2 3 COX-1/2 3 mPGES-1 3 PGE2 biosynthetic pathway (32)(33)(34). Furthermore, sustained ERK1/2 activation is required for maximal PGE2 production (35).…”