Interleukin-6 signal transduction pathways in glial cells

Inflammation is a host response to injury and infection and there is considerable evidence that such processes may be a major cause for neuronal damage leading to neurodegenerative diseases. Interleukin-6 (IL-6) is a key participant in the inflammatory response of the central nervous system (CNS) and it exerts its signals via a membrane-bound (IL-6R) and a soluble form (sIL-6R) of the IL-6 receptor. The sIL-6R is able to initiate IL-6 signaling in cells that lack the membrane-bound form. This process is called trans-signaling and it seems to play a critical role in chronic inflammatory disease progression. Both receptors interact with the membrane-bound receptor subunit gp130 that initiates two different signaling pathways. IL-6 mediated pathologies investigated in transgenic mice are thought to be caused by an imbalance of these two signaling pathways. Through the development of mutant mice lacking the phosphorylation site of one or the other of the two relevant pathways, a distinction between these two signaling pathways can be made. Therefore, the aims of this project are: (1) to determine by the use of primary cell cultures of these mutant mice the contribution of each single signaling pathway to the activation of microglia and astrocytes as well as to determine the contribution of signaling via the membrane-bound versus the soluble receptor. (2) to screen IL-6 treated glial cells by gene expression analysis for differences between astrocytes and microglia and to identify and select target genes that are differently regulated by IL-6 in these two cell types. (3) to investigate in vivo the gene expression and localization of the selected target genes in dependence on IL-6R or sIL-6R activation in transgenic mouse models. To elucidate the regulation and balance of these pathways in glial cells will further increase the knowledge of inflammatory processes in the brain. It can be expected, therefore, that the results of this study will not only provide basic information that can serve for further analysis of the function of IL-6 in the CNS, but will also improve the understanding of trans-signaling processes and will possibly lead to new approaches for the treatment of neurodegenerative diseases that involve inflammatory processes or neurological injury.

Interleukin-6 (IL-6) is a key mediator in the host response to infection or injury in the central nervous system. In the current project, the novel IL-6 regulated gene strawberry notch homolog 2 (Sbno2) was identified. Furthermore, we showed that its expression particularly in astrocytes is not only induced via IL-6 signalling pathways, but also regulated by other pro- inflammatory mediators. Glial cells, especially astrocytes and microglia, have important regulatory functions in the brain. They are the primary defense and immune cells of the central nervous system. They become activated due to fight an infection and preserve or restore a physiological balance, but chronic or severe activation can lead to detrimental effects. One known mediator of this activation is IL-6 and it was shown in mice that transgenic overexpression of IL-6 in astrocytes leads to neurodegeneration. Nevertheless, IL-6 effects can be pro- as well as anti-inflammatory and strongly depend on the responding cell. The current project was aimed at further investigating and understanding the IL-6 function and determining its cell- specific activities. Our studies unveiled a novel, IL-6 regulated gene called Sbno2. In vitro results received from cultured primary murine astrocytes showed a direct response of this gene to IL-6 as well as its regulation by other pro-inflammatory mediators. Furthermore, we found a very short half-life of the Sbno2-encoding ribonucleic acid that suggests a tight expressional control and a possible role of the protein in regulatory functions. In vivo studies revealed an up-regulation in the central nervous system localized mainly to astrocytes and the choroid plexus during systemic inflammation, although selected other cells showed slightly increased expression as well. Our findings, in combination with previous reports and comparisons to related proteins from other organisms suggest a regulatory effect on transcription and a role in gene expression changes during activation of astrocytes. In summary, Sbno2 is a novel inflammatory response gene. The extent of cell-specific factors participating in the Sbno2 gene regulation as well as the number of cells able to express it lead to the assumption that it is involved in complex physiological as well as pathological processes.