PMID: 15240720Jul 9, 2004Paper

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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Hee-Jun NaYoung-Myeong Kim

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 supp...Continue Reading

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Citations

Aug 13, 2015·AMB Express·Seiji ShibasakiTsuyoshi Iwasaki
Jun 15, 2006·Antioxidants & Redox Signaling·Ramendra N Saha, Kalipada Pahan
Sep 10, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Banishree Saha, Dipankar Nandi
Oct 4, 2007·The Journal of Pharmacy and Pharmacology·Kazuhito AsanoTadashi Hisamitsu
Aug 10, 2007·Inflammation·Yamini B TripathiBahram H Arjmandi
Apr 4, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Rasheed AhmadMuhammad Zafarullah
Dec 15, 2005·The Journal of Pharmacology and Experimental Therapeutics·Xiaohua XueAnne Fourie
Apr 4, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Mitch RaponiDavid Atkins
May 16, 2017·Journal of Medicinal Chemistry·Zakey Yusuf BuuhRongsheng E Wang

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