Inhibition of Farnesyltransferase Prevents Collagen-Induced Arthritis by Down-Regulation of Inflammatory Gene Expression through Suppression of p21ras-Dependent NF-κB Activation

Abstract

Farnesylation of p21ras 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 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.

Protein isoprenylation regulates secretion of matrix metalloproteinase 1 from rheumatoid synovial fibroblasts: Effects of statins and farnesyl and geranylgeranyl transferase inhibitors

“…The functional dimers migrate to the nucleus and ligate specific transcriptional response elements. FTIs inhibit NF-B in cells other than RASFs by acting on farnesylated proteins upstream of IKK (39,40). NF-B has been implicated in regulating 2850 ABELES ET AL MMP-1 secretion (15,71,72), and our results suggest that one or more farnesylated proteins regulate the levels of MMP-1 via effects on NF-B.…”

“…Alternatively, protein farnesylation and geranylgeranylation can be specifically blocked by inhibitors of these enzymes. FT inhibitors (FTIs), currently being used in phase III trials for neoplastic disease, were originally designed as chemotherapeutic inhibitors of Ras (37,38), but have also been reported to have antiinflammatory properties both in vitro and in vivo (39,40). FTIs inhibit both MAPK and NF-B in macrophages (39,41), and were beneficial in a mouse model of arthritis (39).…”

“…FT inhibitors (FTIs), currently being used in phase III trials for neoplastic disease, were originally designed as chemotherapeutic inhibitors of Ras (37,38), but have also been reported to have antiinflammatory properties both in vitro and in vivo (39,40). FTIs inhibit both MAPK and NF-B in macrophages (39,41), and were beneficial in a mouse model of arthritis (39). GGT inhibitors (GGTIs) have antiinflammatory properties in cell cultures (42); however, they have been lethal in animal models and are not currently being used in clinical trials (43).…”

Farnesyltransferase inhibitors reduce ras activation and ameliorate acetaminophen-induced liver injury in mice #

“…Recent studies have shown the role of Ras in different inflammatory processes. 25,33 The anti-inflammatory effects of FTIs are important in several diseases, including collagen-induced arthritis 34 and atherosclerosis. 35 In addition, FTIs have been shown to inhibit corneal inflammation by inhibiting macrophage function and decreasing their survival.…”

Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells

“…Cells were incubated with serum-free medium for 4 h and nuclear extracts were prepared as described (Na et al, 2004). A double-stranded AP-1-specific probe (5'-CGCTTGATGAGTCAGCCGGAA-3'; the AP-1 recognition sequence is underlined) was labeled with [γ-32 P]ATP using T4 polynucleotide kinase and purified on a G-50 Sephadex column.…”