Cytokines: Powerful Regulators of Glial Cell Activation

Abstract

It is now clear that cytokines function as powerful regulators of glial cell function in the central nervous system (CNS), either inhibiting or promoting their contribution to CNS pathology. Although these interactions are complex, the availability of animals with targeted deletions of these genes and/or their receptors, as well as transgenic mice in which cytokine expression has been targeted to specific cell types, and the availability of purified populations of glia that can be studied in vitro, has provided a wealth of interesting and frequently surprising data relevant to this activity. A particular feature of many of these studies is that it is the nature of the receptor that is expressed, rather than the cytokine itself, that regulates the functional properties of these cytokines. Because cytokine receptors are themselves modulated by cytokines, it becomes evident that the effects of these cytokines may change dramatically depending upon the cytokine milieu present in the immediate environment. An additional exciting aspect of these studies is the previously underappreciated role of these factors in repair to the CNS. In this review, we focus on current information that has helped to define the role of cytokines in regulating glial cell function as it relates to the properties of microglia and astrocytes.

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…Microglia and astrocytes can, by an NF-kB-mediated mechanism, produce large amounts of proinflammatory cytokines, reactive oxygen species, and excitotoxins. 68 NF-kB can also induce nitric oxide synthase in glial cells resulting in the production of nitric oxide and related neurotoxic reactive oxygen species. 69 A recent study in which irradiated wild-type mice were transplanted with bone marrow from mice lacking inducible nitric oxide synthase provided evidence for an important role for glial nitric oxide in excitotoxin-induced neuronal death.…”

Microarray analysis of IFN-γ response genes in astrocytes

“…More recently however it has been suggested that cytokine activated astrocytes also promote the recovery and repair of CNS function by producing trophic factors for neurons and oligodendrocytes, acting as free radical and excess glutamate scavengers, actively restoring the blood -brain barrier, promoting neovascularization, restoring CNS ionic homeostasis, promoting remyelination and stimulating neurogenesis from neural stem cells (John et al, 2003;Liberto et al, 2004). These studies indicate that astrocytes have important and variable roles in the immune response in the CNS infection.…”

Current insights into the regulation of programmed cell death by NF-κB

“…Although activation of NF-kB in neurons is often protective, its activation in microglia tends to promote neuronal apoptosis, perhaps due to the production of proinflammatory cytokines, reactive oxygen species (ROS) and excitotoxins (John et al, 2003;Mattson and Meffert, 2006). Supporting the idea that NF-kB's well-documented role in inflammation can foster central nervous system (CNS) injury following trauma, targeted inhibition of NF-kB in astroglial cells by tissue-specific expression of the IkBa super-repressor noticeably ameliorated recovery of mice following spinal cord injury and this effect coincided with a reduced production of proinflammatory cytokines (Brambilla et al, 2005).…”