ID: 122: The gp130 cytokines mediate differential signal pathway activation and transcriptional responses in astrocytes versus microglia

Abstract

The gp130 cytokines include IL-6, IL-11, LIF and OSM. These cytokines have important roles in neuroinflammation and neurodevelopment. However, the nature of any cell-specific responses of astrocytes and microglia to this cytokine family and their molecular basis is not well understood. Here, the gp130 family cytokine signal pathway activation and global transcriptional responses were examined in murine astrocytes and microglia in vitro. In astrocytes, OSM-induced STAT1 phosphorylation was significantly greater than for hyperIL-6 (IL-6 linked to the soluble IL-6 receptor) or LIF. However, STAT3 phosphorylation was induced to similar levels for all three cytokines. Conversely, in microglia which lacked the OSMR, hyperIL-6 and LIF but not OSM, induced phosphorylation of STAT3 and only minimal phosphorylation of STAT1. In STAT1 KO astrocytes, OSM conferred a stronger activation of STAT3 compared with WT astrocytes. Transcriptomic analysis of WT and STAT1 KO astrocyte response to OSM, hyperIL-6 or LIF revealed up-regulation and downregulation of many transcripts with OSM > IL-6 > LIF. A dominant IFN-like response to OSM was largely abolished in STAT1 KO astrocytes, suggesting that a large portion of OSM-regulated genes is STAT1-dependent. The gene expression profile of OSM- and hyperIL-6 treated astrocytes was somewhat similar while that for LIF differed the most. Despite signalling via common gp130 pathways, our findings show that specificity is achieved through multiple mechanisms including cell-restricted expression of some receptors, varying strength of signal pathway activation and differential activation of STAT1 and STAT3, which mediate differential gene expression and potential functions by the gp130 cytokines in astrocytes and microglia.