Mechanisms Underlying Specificity in the Biology of the IL-6/gp130 Cytokines in Astrocytes and Microglia

Abstract

The gp130 family of cytokines includes IL-6, OSM, LIF, IL-11, CNTF, CLC/CLF-1 and CT-1. Members of this family are structurally similar and bind to at least one subunit of gp130 in their receptor complexes. Furthermore, they activate common signal transduction pathways, including the JAK/STAT and SHP2 pathways. However, despite these common features, cytokine-specific functions are known to exist. Two types of glial cells, astrocytes and microglia, are involved in the host response against CNS insults and release a variety of inflammatory cytokines and chemokines, including gp130 cytokines. How and whether functional specificity is achieved at the molecular level by the gp130 cytokines in these cells is not well known and was the focus of this project. Our study here suggests that specificity in the actions of the gp130 cytokines can be achieved through a number of mechanisms including differential regulation of the gp130 cytokine genes in response to immunogenic stimuli, the expression and relative abundance of individual receptors, the relative ratio of pY-STAT1:pY-STAT3 and duration of pathway activation, which mediate differential gene expression. Consistent with this, astrocytes showed a dominant STAT1-dependent gene signature in response to OSM, which was reduced for IL-6, and was minimal in response to LIF. It is likely that a combination of these factors will determine the prevailing glial cell-specific response to the gp130 cytokines. We propose a model whereby an interactive network between astrocytes and microglia is formed during CNS inflammation, and the subsequent activation of the JAK/STAT pathway and differences in activation dynamics between STAT1 and STAT3 leads to cell-specific actions of the gp130 cytokines. Manipulation of these contributing factors may allow for alterations in the cellular response and may be a potential therapeutic strategy that targets specific and desired cellular responses, while minimising side effects.