Nuclear factor (
NF)-kappaB is a key regulator of synovial
inflammation. We investigated the effect of local
NF-kappaB inhibition in rat
adjuvant arthritis (AA), using the specific
IkappaB kinase (
IKK)-beta blocking
NF-kappaB essential modulator-binding domain (NBD)
peptide. The effects of the NBD
peptide on human fibroblast-like synoviocytes (FLS) and macrophages, as well as
rheumatoid arthritis (RA) whole-tissue biopsies, were also evaluated. First, we investigated the effects of the NBD
peptide on RA FLS in vitro. Subsequently, NBD
peptides were administered intra-articularly into the right ankle joint of rats at the onset of disease. The severity of
arthritis was monitored over time, rats were sacrificed on day 20, and tissue specimens were collected for routine histology and x-rays of the ankle joints. Human macrophages or RA synovial tissues were cultured ex vivo in the presence or absence of NBD
peptides, and
cytokine production was measured in the supernatant by
enzyme-linked
immunosorbent assay. The NBD
peptide blocked
interleukin (IL)-1-beta-induced
IkappaB alpha phosphorylation and
IL-6 production in RA FLS.
Intra-articular injection of the NBD
peptide led to significantly reduced severity of
arthritis (p < 0.0001) and reduced radiological damage (p = 0.04). This was associated with decreased synovial cellularity and reduced expression of
tumor necrosis factor (
TNF)-alpha and IL-1-beta in the synovium. Incubation of human macrophages with NBD
peptides resulted in 50% inhibition of IL-1-beta-induced
TNF-alpha production in the supernatant (p < 0.01). In addition, the NBD
peptide decreased
TNF-alpha-induced
IL-6 production by human RA synovial tissue biopsies by approximately 42% (p < 0.01). Specific
NF-kappaB blockade using a small
peptide inhibitor of
IKK-beta has anti-inflammatory effects in AA and human RA synovial tissue as well as in two important cell types in the pathogenesis of RA: macrophages and FLS. These results indicate that
IKK-beta-targeted
NF-kappaB blockade using the NBD
peptide could offer a new approach for the local treatment of
arthritis.