Citreorosein Inhibits Production of Proinflammatory Cytokines by Blocking Mitogen Activated Protein Kinases, Nuclear Factor-kappa B and Activator Protein-1 Activation in Mouse Bone Marrow-Derived Mast Cells

Abstract

Citreorosein (CIT), an anthraquinone component of Polygoni cuspidati (P. cuspidati) radix, suppressed gene expression of proinflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1 beta in mouse bone marrow-derived mast cells (BMMCs) stimulated with phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187. To investigate the molecular mechanisms underlying CIT inhibition of the pro-inflammatory cytokine production, its effects on the activation of both nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinases (MAPKs) were assessed. CIT attenuated phosphorylation of the MAPKs including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAP kinase and c-Jun NH2-terminal kinase (JNK). Furthermore, CIT strongly inhibited DNA binding activity of NF-kappa B through the inhibition of phosphorylation and degradation of inhibitor of kappaB (1 kappa B) as well as activator protein-1 (AP)-1 through the reduction of phosphorylation of c-Jun. These results demonstrate that CIT inhibits proinflammatory cytokines production through the inhibition of both MAPKs and AKT-mediated 1 kappa B kinase (IKK) phosphorylation and subsequent inhibition of transcription factor NF-kappa B activation, thereby attenuating the production of proinflammatory cytokines.