Nordihydroguaiaretic acid suppresses the lipopolysaccharide-induced activation of macrophage through the down-regulation of TAK1

Abstract

Nordihydroguaiaretic acid (NDGA), a well-known lipoxygenase inhibitor, exerts pleiotropic effects on various cellular events. It has also been known that NDGA suppresses immune response in lipopolysaccharide (LPS)challenged immune cells. Although the immunosuppressive activity of NDGA was suggested to be related with its antioxidant activity, the precise mechanism for its diverse effects on immune system has not been clarified yet. Since transforming growth factorÁbÁactivated kinase 1 (TAK1) is an essential intracellular signaling component in mediating the immune responses of macrophage and lymphocytes, we asked whether NDGA has specific effect on TAK1 signaling pathway. In this study, we examined the immunosuppressive activity of NDGA in murine macrophage cell line (RAW 264.7) as well as the changes in TAK1 after the NDGA challenge. Our results clearly showed that the LPS-induced iNOS, COX-2, and tumor necrosis factor a (TNF-a) expressions were suppressed and TAK1 was also significantly down-regulated in the presence of NDGA. However, the messenger ribonucleic acid (mRNA) level of TAK1 was not changed. Instead, the protein level was significantly decreased by the treatment of NDGA, and the specific proteasome inhibitor was able to block the decrease in TAK1 level. This result implied the involvement of protein degradation pathway in down-regulation of TAK1 by NDGA. Because NDGA also suppressed c-Jun NH2-terminal protein kinase (JNK) activation caused by LPS treatment in correlation with the decrease in TAK1 level, the immunosuppression exerted by NDGA seemed correlated with its down-regulating effect on TAK1 together with the blockage of NF-kB signaling.