Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21 ras-dependent NF-κB activation

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, Young Myeong Kim

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Farnesylation of p21ras 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 p21ras farnesylation and examined the effects of this inhibitor in the settings of inflammation and arthritis. LB42708 suppressed NF-κB activation and iNOS promoter activity by suppressing the I-κB kinase activity and I-κBα degradation. The inhibitor suppressed the expression of inducible NO synthase, cyclooxygenase-2, TNF-α, and IL-1β 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-α, and IL-1β 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-κB kinase activity and subsequent suppression of NF-κB-dependent inflammatory gene expression through the suppression of p21ras farnesylation. Together, these findings reveal that the inhibitory effect of LB42708 on p21ras-dependent NF-κB activation may have potential therapeutic value for arthritis and other inflammatory diseases.

Original languageEnglish
Pages (from-to)1276-1283
Number of pages8
JournalJournal of Immunology
Volume173
Issue number2
Publication statusPublished - 2004 Jul 15

Fingerprint

Proto-Oncogene Proteins p21(ras)
Farnesyltranstransferase
Experimental Arthritis
Gene Expression Regulation
Prenylation
Down-Regulation
Arthritis
Cyclooxygenase 2
Interleukin-1
Nitric Oxide Synthase
Phosphotransferases
Osteoblasts
Dinoprostone
Growth Hormone
Inhibitory Concentration 50
Cultured Cells
Intercellular Signaling Peptides and Proteins
Anti-Inflammatory Agents
Macrophages
Inflammation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Na, Hee Jun ; Lee, Seon Jin ; Kang, Yun Chul ; Cho, Young Lai ; Nam, Woo Dong ; Kim, Peter K.M. ; Ha, Kwon Soo ; Chung, Hun Taeg ; Lee, Hansoo ; Kwon, Young Guen ; Koh, Jong Sung ; Kim, Young Myeong. / Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21 ras-dependent NF-κB activation. In: Journal of Immunology. 2004 ; Vol. 173, No. 2. pp. 1276-1283.
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title = "Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21 ras-dependent NF-κB activation",
abstract = "Farnesylation of p21ras 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 p21ras farnesylation and examined the effects of this inhibitor in the settings of inflammation and arthritis. LB42708 suppressed NF-κB activation and iNOS promoter activity by suppressing the I-κB kinase activity and I-κBα degradation. The inhibitor suppressed the expression of inducible NO synthase, cyclooxygenase-2, TNF-α, and IL-1β 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-α, and IL-1β 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-κB kinase activity and subsequent suppression of NF-κB-dependent inflammatory gene expression through the suppression of p21ras farnesylation. Together, these findings reveal that the inhibitory effect of LB42708 on p21ras-dependent NF-κB activation may have potential therapeutic value for arthritis and other inflammatory diseases.",
author = "Na, {Hee Jun} and Lee, {Seon Jin} and Kang, {Yun Chul} and Cho, {Young Lai} and Nam, {Woo Dong} and Kim, {Peter K.M.} and Ha, {Kwon Soo} and Chung, {Hun Taeg} and Hansoo Lee and Kwon, {Young Guen} and Koh, {Jong Sung} and Kim, {Young Myeong}",
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Na, HJ, Lee, SJ, Kang, YC, Cho, YL, Nam, WD, Kim, PKM, Ha, KS, Chung, HT, Lee, H, Kwon, YG, Koh, JS & Kim, YM 2004, 'Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21 ras-dependent NF-κB activation', Journal of Immunology, vol. 173, no. 2, pp. 1276-1283.

Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21 ras-dependent NF-κB activation. / Na, Hee Jun; Lee, Seon Jin; Kang, Yun Chul; Cho, Young Lai; Nam, Woo Dong; Kim, Peter K.M.; Ha, Kwon Soo; Chung, Hun Taeg; Lee, Hansoo; Kwon, Young Guen; Koh, Jong Sung; Kim, Young Myeong.

In: Journal of Immunology, Vol. 173, No. 2, 15.07.2004, p. 1276-1283.

Research output: Contribution to journalArticle

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T1 - Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21 ras-dependent NF-κB activation

AU - Na, Hee Jun

AU - Lee, Seon Jin

AU - Kang, Yun Chul

AU - Cho, Young Lai

AU - Nam, Woo Dong

AU - Kim, Peter K.M.

AU - Ha, Kwon Soo

AU - Chung, Hun Taeg

AU - Lee, Hansoo

AU - Kwon, Young Guen

AU - Koh, Jong Sung

AU - Kim, Young Myeong

PY - 2004/7/15

Y1 - 2004/7/15

N2 - Farnesylation of p21ras 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 p21ras farnesylation and examined the effects of this inhibitor in the settings of inflammation and arthritis. LB42708 suppressed NF-κB activation and iNOS promoter activity by suppressing the I-κB kinase activity and I-κBα degradation. The inhibitor suppressed the expression of inducible NO synthase, cyclooxygenase-2, TNF-α, and IL-1β 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-α, and IL-1β 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-κB kinase activity and subsequent suppression of NF-κB-dependent inflammatory gene expression through the suppression of p21ras farnesylation. Together, these findings reveal that the inhibitory effect of LB42708 on p21ras-dependent NF-κB activation may have potential therapeutic value for arthritis and other inflammatory diseases.

AB - Farnesylation of p21ras 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 p21ras farnesylation and examined the effects of this inhibitor in the settings of inflammation and arthritis. LB42708 suppressed NF-κB activation and iNOS promoter activity by suppressing the I-κB kinase activity and I-κBα degradation. The inhibitor suppressed the expression of inducible NO synthase, cyclooxygenase-2, TNF-α, and IL-1β 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-α, and IL-1β 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-κB kinase activity and subsequent suppression of NF-κB-dependent inflammatory gene expression through the suppression of p21ras farnesylation. Together, these findings reveal that the inhibitory effect of LB42708 on p21ras-dependent NF-κB activation may have potential therapeutic value for arthritis and other inflammatory diseases.

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