Advisory Committee Chair
Etty (Tika) N Benveniste
Advisory Committee Members
Michael Brenner
Jim Collawn
Stuart J Frank
Lori McMahon-Wakefield
Document Type
Dissertation
Date of Award
2009
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Astrocytes and microglia are specialized glial cells of the Central Nervous System (CNS) that modulate neural activity and regulate immunological and inflammatory events. These cells perform their functions, in part, through the secretion of soluble mediators such as cytokines and chemokines. However, in response to the same neurological insult or inflammatory stimuli, the responses of these cells can vary greatly. This notion of differential responses was examined in our studies using Oncostatin M (OSM). OSM is a member of the IL-6 family of cytokines, which can be produced by microglia, astrocytes, neurons, and infiltrating leukocytes in the CNS, and is upregulated in a number of neuroinflammatory diseases. However, its effects within the CNS are not well understood. In astrocytes, OSM induces the expression of Suppressor Of Cytokine Signaling-3 (SOCS-3), a potent negative regulator of inflammatory cytokine signaling. However, OSM does not induce SOCS-3 expression in microglia. Similarly, OSM induces the production of the pro-inflammatory cytokine tumor necrosis factor-alpha; (TNF-alpha;) and inducible nitric oxide synthase (iNOS) from microglia, which are not expressed by astrocytes when exposed to OSM. The mechanisms of OSM-induced SOCS-3 and OSM-induced TNF-alpha; and iNOS expression were examined in astrocytes and microglia, respectively. In astrocytes, OSM utilizes the JAK/STAT and MAPK pathways to induce SOCS-3 expression. In microglia, OSM induces TNF-alpha; and iNOS expression via the NF-kappa B pathway, which also partially requires the intermediate production of TNF-alpha;. Interestingly, OSM does not activate the JAK/STAT pathway in microglia. Supernatants from OSM-treated microglia impair neuronal cell viability, which can be rescued by co-treating microglia with IL-27, a cytokine that inhibits OSM-mediated NF-kappa B activation and production of TNF-alpha; and NO. Therefore, OSM exposure of astrocytes and microglia leads to differential activation of signaling pathways and gene expression, underscoring the importance of cell-type-specific modulation in immunotherapies.
Recommended Citation
Baker, Brandi Janece, "Oncostatin M-induced Gene Expression and Regulation in Astrocytes and Microglia" (2009). All ETDs from UAB. 1086.
https://digitalcommons.library.uab.edu/etd-collection/1086