Toll-like Receptor 4-mediated Immunoregulation by the Aqueous Extract of Mori Fructus

The aqueous extract of Mori Fructus (MF) exerts a change of phenotype and a cytoprotective effect in macrophages. The present study was carried out to investigate the immunomodulating activity of MF on the expression of nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), co-stimulatory molecules and also interferon-gamma (IFN-gamma) in macrophages and splenocytes. Toll-like receptor 4 (TLR4) is a promising molecular target for immune-modulating drugs. It was hypothesized that one possible upstream signaling pathway leading to immuno-regulation of MF may be mediated by TLRs. Multiple signaling molecules (NF-kappa B, ERK1/2, p38 and JNK) of the TLR4 signaling pathway were also detected. It was found that MF increased NO production and TNF-a secretion in RAW 264.7 and peritoneal macrophages, co-stimulatory molecules expression in peritoneal macrophages and IFN-gamma expression in splenocytes. Further studies indicated that MF could significantly induce the phosphorylation of signal molecules of MAPKs and the degradation of I kappa B alpha which finally led to the activation and nuclear translocation of nuclear factor-kappa B (NF-kappa B) for the target gene expression. All those notions disclosed that the aqueous extract MF is a new TLR4 activator, which induces a Th1 immune response as a consequence of induction of cytokines secretion, especially TNF-alpha and IFN-gamma. Copyright 2009 John Wiley & Sons, Ltd.