Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis.
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.
Nah
Seong-Su
SS
Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University, College of Medicine, Bongmyeong-Dong, Choenan, Republic of Korea.
Won
Hye-Jin
HJ
Ha
Eunyoung
E
Kang
Insug
I
Cho
Hong Yon
HY
Hur
Sook-Jin
SJ
Lee
Sang-Hoon
SH
Baik
Hyung Hwan
HH
D001172:Arthritis, Rheumatoid / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
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