Inhibition of Inflammatory Cytokine Production from Rheumatoid Synovial Fibroblasts by a Novel I{kappa}B Kinase Inhibitor.
The Journal of pharmacology and experimental therapeutics 2010 Jan 6; In press
Tsuchiya A, Imai K, Asamitsu K, Waguri-Nagaya Y, Otsuka T, Okamoto T
1 Department of Molecular and Cellular Biology, Nagoya City University Grad. Sch. Medical Sciences;
Nuclear factor kappa B (NF-kappaB) is involved in pathophysiology of Rheumatoid arthritis (RA) and is considered to be a feasible molecular target in treating patients. In the RA joint tissues activation of NF-kappaB is often observed together with high amounts of proinflammatory cytokines, TNFalpha and IL-1beta. TNFalpha and IL-1beta are known to stimulate NF-kappaB signalling and produced as the effect of NF-kappaB signalling, thus forming a vicious cycle leading to a self-perpetuating nature of rheumatoid inflammation and expansion of such inflammatory response to other joints. Since a kinase called IkappaB kinase (IKK) is involved in the NF-kappaB activation cascade, we examined the effect of a novel IKK inhibitor, (7-[2-(cyclopropyl-methoxy)-6-hydroxyphenyl]-5-[(3S)-3-piperidinyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride) (CHPD), on the production of inflammatory cytokines from rheumatoid synovial fibroblasts (RSF). TNFalpha stimulation induced production of inflammatory cytokines such as IL-6 and IL-8 in RSF and the extents of IL-6 and IL-8 induction were dramatically reduced by CHPD under non-cytotoxic concentrations. Similarly, expression of il-6 and il-8 genes was significantly reduced by CHPD. In addition, ChIP assays revealed that the DNA-binding of NF-kappaB (p65) to il-8 promoter in RSF was induced after TNFalpha stimulation, and upon CHPD treatment to RSF for 1 h the NF-kappaB binding to il-8 promoter was significantly decreased. In this paper, we have demonstrated that an IKKbeta inhibitor, CHPD, acts as an effective inhibitor for the production of inflammatory cytokines in response to proinflammatory cytokines. These findings indicate that such IKKbeta inhibitor could be a feasible candidate of anti-rheumatic drug.
Keywords: I{kappa}B Rheumatoid arthritis