Abstract
N-tosyl-l-phenylalanine chloromethyl ketone (TPCK) is known to inhibit NF-κB activation and the expression of inflammation mediators in cultured cells. We measured the potential of TPCK to inhibit the pathogenesis of collagen-induced arthritis by blocking NF-κB activation. Arthritis was induced in DBA/1J mice by the injection of bovine type II collagen in adjuvant on days 0 and 14. Mice received either TPCK (3 or 10 mg/kg, i.p.) or vehicle three times a week for 3 weeks starting on day 21. TPCK moderately reduced clinical disease activity scores, whereas it markedly suppressed histological indications of joint destruction. In vitro production of tumor necrosis factor-α, interleukin-6, and monocyte chemotactic protein-1 from lipopolysaccharide-stimulated spleen cells was also reduced by in vivo treatment with TPCK. Proliferation of cells isolated from spleen or draining lymph nodes and production of interferon-γ and interleukin-17 in response to stimulation with type II collagen was decreased by TPCK. Moreover, nuclear NF-κB activity induced by collagen immunization was significantly reduced in mice treated with TPCK. Finally, osteoclast differentiation of bone marrow cells induced by macrophage colony-stimulating factor and receptor activator of NF-κB ligand was completely inhibited by TPCK. These results indicate that TPCK attenuates collagen-induced arthritis and bone erosion by suppressing NF-κB activation and thus expression of inflammatory and osteoclastogenic genes.
Original language | English (US) |
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Pages (from-to) | 108-113 |
Number of pages | 6 |
Journal | European Journal of Pharmacology |
Volume | 595 |
Issue number | 1-3 |
DOIs | |
State | Published - Oct 24 2008 |
Keywords
- Collagen-induced arthritis
- Cytokine
- Inflammation
- NF-κB
- Rheumatoid arthritis
- Tosylphenylalanyl chloromethyl ketone
ASJC Scopus subject areas
- Pharmacology