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Inhibition of Farnesyltransferase Prevents Collagen-Induced Arthritis by Down-Regulation of Inflammatory Gene Expression through Suppression of p21^ras-Dependent NF-B Activation¹

Hee-Jun Na^*, Seon-Jin Lee^*, Yun-Chul Kang^*, Young-Lai Cho^*, Woo-Dong Nam, Peter K. M. Kim, Kwon-Soo Ha^*, Hun-Taeg Chung, Hansoo Lee^¶, Young-Guen Kwon^||, Jong Sung Koh^# and Young-Myeong Kim^2,*

^* Vascular System Research Center and Department of Molecular and Cellular Biochemistry, and Department of Orthopaethic Surgery, School of Medicine, Kangwon National University, Chunchon, Kangwon-do, Korea; Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213; Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Chonbuk, Korea; ^¶ Department of Biology, College of Natural Science, Chunchon, Kangwon-do, Korea; ^|| Department of Biochemistry, College of Science, Yonsei University, Seoul, Korea; and ^# Drug Discovery, Research, and Development Center, LG Life Sciences, Taejon, Korea

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 IC₅₀ 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-B activation and iNOS promoter activity by suppressing the I-B kinase activity and I-B degradation. The inhibitor suppressed the expression of inducible NO synthase, cyclooxygenase-2, TNF-, and IL-1 and the production of NO and PGE₂ 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-, and IL-1 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-B kinase activity and subsequent suppression of NF-B-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-B activation may have potential therapeutic value for arthritis and other inflammatory diseases.

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