title: Enhancement of PLGF production by 15-(S)-HETE via PI3K-Akt, NF-κB and COX-2 pathways in rheumatoid arthritis synovial fibroblast.
abstract: Metabolites from arachidonic acids play the pivotal roles in inflammatory arthritis. Arachidonic acid could be metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) to produce the bioactive eicosanoids. Although the down-stream products of COX including prostaglandin E2 are well-known inflammatory stimulators, the role of LOX products in inflammatory arthritis is still unclear. Here we found that the downstream product of 15-LOX, 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), can enhance the expression of placenta growth factor (PLGF), which is recently considered to play an important role in rheumatoid arthritis. 15-(S)-HETE increased the expression of PLGF in human rheumatoid arthritis synovial fibroblasts in a time-dependent and concentration-dependent manner. PI3K-Akt, NF-κB signaling pathways were involved in the potentiation effects of 15-(S)-HETE. In addition, COX-2 was up-regulated by the treatment of 15-(S)-HETE and the increase of COX-2 expression participated in 15-(S)-HETE-induced PLGF expression, which was confirmed by COX-2 shRNA or pharmacological COX-2 inhibitor. Moreover, it was found that treatment of prostaglandin E2 (PGE2), which was the main down-stream metabolite of COX-2, increased the expression of PLGF. EP1, EP2, EP3 and EP4 agonists could up-regulate PLGF as well. In animal studies, we found that the adjuvant-induced expression of PLGF and COX-2 was inhibited in 15-LOX knockout mice. These results indicated that PLGF up-regulation by 15-LOX downstream product may be involved in inflammatory arthritis.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taiwan (100) Taipei, Taiwan.
authors.forename: Ming-Yueh
authors.initials: MY
authors.lastname: Wu
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Yang
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Lin
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
authors.forename: Yung-Cheng
authors.initials: YC
authors.lastname: Chiu
authors.forename: Houng-Chi
authors.initials: HC
authors.lastname: Liou
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D055786:Gene Knockout Techniques; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D016328:NF-kappa B; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D034741:RNA, Small Interfering; D000072483:Placenta Growth Factor; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015232:Dinoprostone
keywords: 15-lipoxygenase; COX-2; Inflammation; PLGF; Synovial fibroblasts