SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia

Stromal cell-derived factor-1 (SDF-1), also known as CXCL12, and its receptor CXC chemokine receptor 4 (CXCR4) express in various kinds of cells in central nervous system. The SDF-1/CXCR4 signaling pathway is regulated by diverse biological effects. SDF-1 is up-regulated in the ischemic penumbra following stroke and has been known to be associated with the homing of bone marrow cells to injury. However, the effect of SDF-1 alpha/CXCR4 on cytokine production in microglia is mostly unknown. Here, we demonstrated that SDF-1 alpha enhanced IL-6 production in both primary cultured microglia and BV-2 microglia. We further investigated the signaling pathway involved in IL-6 production stimulated by SDF-1 alpha in microglia. SDF- increased IL-6 production in both protein and mRNA levels. These effects were attenuated by ERK, phosphatidylinositol 3-kinase (PI3K), NF-kappa B inhibitors, and I kappa B protease inhibitor. Stimulation of microglia with SDF-1 alpha also increased Akt and ERK1/2 phosphorylation. In addition, SDF-1 alpha treatment also increased I kappa B kinase alpha/beta (IKK alpha/beta) phosphorylation, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation at Ser(276), translocation of p65 and p50 from cytosol to nucleus and kappa B-luciferase activity. Moreover, SDF-1 alpha-mediated increase of kappa B-luciferase activity was inhibited by pre-transfection of DN-p85, DN-Akt or DN-ERK2. Increase of IKK alpha/beta phosphorylation and binding of p65 and p50 to the NF-kappa B element were both antagonized by PI3K and ERK inhibitors. Our results demonstrate a mechanism linking SDF-1 alpha and IL-6. and provide additional support for the notion that SDF-1 alpha plays a regulatory role in microglia activation. (C) 2009 Elsevier B.V. All rights reserved.