Down-regulation of IL-6 production by astaxanthin via ERK-, MSK-, and NF-κB-mediated signals in activated microglia

Abstract

In this study, we investigated the effect of astaxanthin on IL-6 in activated microglial cells because excessive interleukin-6 (IL-6) production by activated brain microglia has been linked to many neurological disorders and proper regulation of IL-6 is critical for maintaining brain homeostasis. Astaxanthin inhibited lipopolysaccharide (LPS)-stimulated IL-6 mRNA and protein in BV-2 microglial cells. Moreover, LPS-induced p-IKKα, p-IκBα, and p-NF-κB p65 levels were all suppressed by astaxanthin. The translocation of p-NF-κB p65 from the cytosol into the nucleus and transcriptional activity were inhibited by astaxanthin. IL-6 expression and NF-κB transcriptional activation were inhibited by astaxanthin, as well as inhibitors of NF-κB and MAPK in LPS-stimulated BV-2 microglial cells. Consistent with these findings, astaxanthin down-regulated the activation of p-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and p-mitogen- and stress-activated protein kinase 1(p-MSK1), but not of p-c-jun N-terminal kinase (p-JNK). Astaxathin also decreased IL-6 mRNA and protein levels in LPS-stimulated primary microglial cells, RAW264.7 macrophages, and peritoneal macrophages. In addition, IL-6 suppression through astaxanthin-induced down-regulation of p-ERK1/2, p-MSK1, and p-NF-κB p65 occurred in microglial cells stimulated with LPS or stromal derived factor (SDF)-1α. Astaxathin also inhibited the secretion and mRNA expression of IL-6 in SDF-1α-stimulated microglial cells. SDF-1α-stimulated ERK1/2, MSK1, and NF-κB p65 phosphorylation were reduced by astaxanthin. Therefore, our results suggest that astaxanthin regulates IL-6 production through a p-ERK1/2-MSK-1- and p-NF-κB p65-dependent pathway in activated microglial cells.