A Novel Synthetic Compound, YH-1118, Inhibited LPS-Induced Inflammatory Response by Suppressing I kappa B Kinase/NF-kappa B Pathway in Raw 264.7 Cells

Abstract

For the search of a potent first-in-class compound to inactivate macrophages responsible for inflammatory responses, in the present study, we investigated the anti-inflammatory effects of YH-1118, a novel synthetic compound, in a lipopolysaccharide (LPS)-stimulated mouse macrophage cell line, Raw 264.7. YH-1118 inhibited LPS-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression at both the protein and mRNA levels. The suppression of LPS-induced iNOS expression by YH-1118 was mediated via nuclear factor kappa B (NF-kappa B), but not activator protein-1 (AP-1) transcription factor. This was supported by the finding that YH-1118 attenuated the phosphorylation of inhibitor of kappa B alpha (I kappa B alpha) and nuclear translocation and DNA binding activity of NF-kappa B. Through the mechanisms that YH-1118 inhibited the activation of I kappa B kinases (IKKs), upstream activators of NF-kappa B, or p38 MAPK, YH-1118 significantly suppressed LPS-induced production of pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 beta (IL-1 beta), and IL-6 (p < 0.05). In conclusion, our results suggest that YH-1118 inhibits LPS-induced inflammatory responses by blocking IKK and NF-kappa B activation in macrophages, and may be a therapeutic candidate for the treatment of various inflammatory diseases.