Inhibition of TNF-alpha-mediated inflammatory responses by a benzodioxolylacetylamino-linked benzothiazole analog in human fibroblast-like synoviocytes

Abstract

The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-kappa B. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-kappa B activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537 inhibited the nuclear translocation and the DNA binding of NF-kappa B subunits, which correlated with the inhibitory effects on IKK phosphorylation and I kappa B alpha degradation in TNF-alpha-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-alpha-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-kappa B ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-kappa B pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis. (C) 2011 Elsevier Inc. All rights reserved.