Publikationsserver der RWTH Aachen University
Immunomodulatory function of astrocytes characterization and regulation of postanoid metabolism and cytokine synthesis
Abstract
dc:descriptionGlial cells in the CNS are supportive and nutritive for neurons. Furthermore, they regulate the ion milieu and energy homeostasis in the CNS. During development, they stimulate via growth factors and other developmentally active agents the differentiation of neural systems. Importantly, they are the key regulators of extracellular glutamate levels. In addition to these many functions, astrocytes are actively incorporated in the control of neuroinflammation and neurodegeneration. Besides microglia, astrocytes appear to play a dynamic role during brain inflammation and neuronal degeneration. Retinoic acid has recently been shown to be involved in the regulation of neuroinflammatory processes. Since reactive astrocytes produce a distinct set of inflammatory cytokines (IL-1b, IL-6, IFN-g, and TNF-a) and prostaglandins, they are predestinated to initiate, perpetuate, and terminate immunological processes in the brain. Thus, astroglial-derived immunomodulatory factors are integrated in the complex scenario of glia-glia and glia-neuron cell to cell communication during pathological processes. I have shown for the first time in detail that mouse neonatal cortical astroglia is capable to express and regulate several cytokines and the complete enzymatic machinery of prostanoid synthesis and degradation upon stimulation with lipopolysaccharides (LPS) which mimics a bacterial infection. I have presented data revealing that astrocytes from different brain regions possess distinct local differences in the baseline expression of pro-inflammatory mediators and sensitivity upon inflammatory stimuli. Treatment with LPS caused a massive up-regulation of and enzymes responsible for prostaglandin E2 (PGE2) formation as well as a down-regulation of such enzymes which catalyze PGE2 degradation. As a consequence of LPS application, we observe a rapid and temporarily restricted PGE2 release from cortical astrocytes. This clearly highlights the importance of astrocytes in circumscribed inflammatory areas in the CNS and raises the question to what extent astroglia is pivotal for the further regulation of immuncompetent cells and their activity. Further experimental approaches suggest that nuclear hormones, including estrogen (E), progesterone (P) and retinoic acid (RA) can function as important immune-modulators. They also take part in the regulation of prostanoid and cytokine synthesis in astrocytes. Astrocytes were shown to express several subtypes of E/P and RA receptors. The simultaneous administration of sex steroids or RA significantly attenuated many of the observed LPS effects on cytokine and prostanoid metabolism, thus, yielding a considerable reduction of TNF-a, IL-18, COX-2 expression and PGE2 release. In conclusion, my data suggest an active role for astroglia in brain cytokine and PGE2 synthesis under neuropathological conditions. Sex steroids and retinoic acid appear to be very effective in the suppression of TNF-alpha, IL-18 and PGE2 production and might, therefore, be a useful tool for clinical treatment of neuroinflammatory processes in the brain.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2009
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Johann, Sonja
- Contributors dc:contributor
-
- Wagner, Hermann
Subjects
dc:subject × 9Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- eng