THE EFFECTS OF THE CIS- AND TRANS-GNETIN H ISOLATED FROM PAEONIA SUFFRUTICOSA AND A SYNTHETIC AURONE, (Z)-2-((5-(HYDROXYLMETHYL) FURAN-2-YL) METHYLENE) BENZOFURAN-3(2H)-ONE ON NF-κB AND MAPK PATHWAYS IN LPS-STIMULATED MACROPHAGES

Abstract

Inflammation is central to many disease processes such as autoimmunity and chronic inflammatory diseases, yet there are relatively few classes of compounds used as anti-inflammatory drugs. Nonsteroidal anti-inflammatory drugs (NSAIDS) and steroids have been used for many years and recently, biotherapeutic modifiers such as monoclonal antibodies and fusion proteins were developed to treat chronic inflammation, however, many patients experience serious side effects, and are thus reserved for devastating inflammatory diseases such as rheumatoid arthritis and ankylosing spondylitis. Recently, more attention has been given to herbal ingredients that have been used to treat inflammatory diseases. This is due to safety and efficacy of the herbal medicine, lower risk of side effects, lower costs, and potential use as adjunct treatments to Western medicines. In this study, cis- and trans-gnetin H and a synthetic aurone, (Z)-2-((5-(hydroxymethyl) furan-2-yl) methylene) benzofuran-3(2H)-one (aurone 1) were evaluated for their mechanism of action in suppressing the intracellular proinflammatory pathways that regulate inflammatory cytokines in activated macrophages. All three compounds were found to suppress the cytokines, TNF-α, IL-1β, and IL-8, through inhibition of IKK-β which is a key regulator of the NF-κB pathway. The effects of cis- and trans-gnetin H on MAPK pathway was also investigated in THP-1 cells and showed both gnetin H compounds were able to suppress SAPK/JNK but ERK 1/2 were suppressed only by cis-gnetin H. Neither gnetin H were able to suppress p38 phosphorylation. Further studies using a murine cell line confirmed the effects of aurone 1 in suppressing the NF-κB pathway by concentration-dependent suppression of iNOS as well as the production of NO which are regulated by the NF-κB pathway. The investigation of the effects of aurone 1 on MAPK mediators from human and murine macrophages suggested selective inhibition NF-κB signaling without affecting the MAPK pathway. Together, these findings suggest the gnetin H compounds and aurone 1 are anti-inflammatory compounds with therapeutic potential for the possible treatment of chronic inflammatory diseases.