Received for publication July 21, 2004.
Revised August 6, 2004.
Accepted for publication August 9, 2004.

Attenuation of Murine Collagen-Induced Arthritis by a Novel, Potent and Selective Small Molecule Inhibitor of IB Kinase 2, TPCA-1, Occurs via Reduction of Proinflammatory Cytokines and Antigen-Induced T Cell Proliferation

Abstract

Demonstration that IB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-B (NF-B)-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)- and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis. In the present study, we demonstrate that a novel, potent (IC₅₀ = 17.9 nM) and selective inhibitor of human IKK-2, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), inhibits lipopolysaccharide (LPS)-induced human monocyte production of TNF-, IL-6, and IL-8 with an IC₅₀ = 170 - 320 nM. Prophylactic administration of TPCA-1 at 3, 10 or 20 mg/kg, i.p., b.i.d, resulted in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d., were comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. p65 nuclear localization, as well as levels of IL-1, IL-6, TNF-, and interferon(IFN)- were significantly reduced in the paw tissue of TPCA-1-treated and etanercept-treated mice. In addition, administration of TPCA-1 in vivo resulted in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduced the severity of CIA, as did etanercept administration at 12.5 mg/kg, i.p., every other day. These results suggest that reduction of proinflammatory mediators, and inhibition of antigen-induced T cell proliferation, are mechanisms underlying the attenuation of CIA by the IKK-2 inhibitor, TPCA-1.

Key words: IKK-2, antigen-induced T cell proliferation, collagen-induced arthritis, etanercept, proinflammatory mediators, small molecule inhibitor

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