Nuclear factor-kappaB (
NF-kappaB) is involved in the 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 the proinflammatory
cytokines tumor necrosis factor (
TNF)alpha and
interleukin (IL)-1beta.
TNFalpha and IL-1beta are known to stimulate
NF-kappaB signaling and are produced as the effect of
NF-kappaB signaling, thus forming a vicious cycle leading to a self-perpetuating nature of rheumatoid
inflammation and expansion of such inflammatory response to other joints. Because a
kinase called
IkappaB kinase complex (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 extent of
IL-6 and
IL-8 induction was dramatically reduced by CHPD under noncytotoxic concentrations. Likewise, expression of
il-6 and
il-8 genes was significantly reduced by CHPD. In addition,
chromatin immunoprecipitation assays revealed that the
DNA binding of
NF-kappaB (p65) to
il-8 promoter in RSF was induced after
TNFalpha stimulation and that, upon CHPD treatment to RSF for 1 h, the
NF-kappaB binding to
il-8 promoter was significantly decreased. Here, 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 a IKKbeta inhibitor could be a feasible candidate for an
antirheumatic drug.