title: Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21(ras)-dependent NF-kappaB activation.
abstract: Farnesylation of p21(ras) is an important step in the intracellular signaling pathway of growth factors, hormones, and immune stimulants. We synthesized a potent and selective farnesyltransferase inhibitor (LB42708) with IC(50) values of 0.8 nM in vitro and 8 nM in cultured cells against p21(ras) farnesylation and examined the effects of this inhibitor in the settings of inflammation and arthritis. LB42708 suppressed NF-kappaB activation and iNOS promoter activity by suppressing the I-kappaB kinase activity and I-kappaBalpha degradation. The inhibitor suppressed the expression of inducible NO synthase, cyclooxygenase-2, TNF-alpha, and IL-1beta and the production of NO and PGE(2) in immune-activated macrophages and osteoblasts as well as LPS-administrated mice. Furthermore, in vivo administration of LB42708 significantly decreased the incidence and severity of arthritis as well as mRNA expression of inducible NO synthase, cyclooxygenase-2, TNF-alpha, and IL-1beta in the paws of collagen-induced arthritic mice compared with controls. These observations indicate that the anti-inflammatory and antiarthritic effects of the farnesyltransferase inhibitor may be ascribed to the inhibition of I-kappaB kinase activity and subsequent suppression of NF-kappaB-dependent inflammatory gene expression through the suppression of p21(ras) farnesylation. Together, these findings reveal that the inhibitory effect of LB42708 on p21(ras)-dependent NF-kappaB activation may have potential therapeutic value for arthritis and other inflammatory diseases.
authors.affiliation: Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwon-do, Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Na
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Yun-Chul
authors.initials: YC
authors.lastname: Kang
authors.forename: Young-Lai
authors.initials: YL
authors.lastname: Cho
authors.forename: Woo-Dong
authors.initials: WD
authors.lastname: Nam
authors.forename: Peter K M
authors.initials: PK
authors.lastname: Kim
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.forename: Hun-Taeg
authors.initials: HT
authors.lastname: Chung
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.forename: Jong Sung
authors.initials: JS
authors.lastname: Koh
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016328:NF-kappa B; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D015232:Dinoprostone