Neuroinflammation is a prominent feature of the CNS response to acute injury, infection, and chronic neurodegeneration, and represents a potential target for treating CNS disorders, including Alzheimer's disease (AD). Elaboration of-inflammatory responses depends on key molecular players that drive interactions among cells. One of these players is IL-1beta, a proinflammatory cytokine implicated in acute CNS inflammation and AD. Another player is prostaglandin E2 (PGE2) produced by the inflammation-responsive protein, cyclooxygenase-2 (COX-2). PGE2 is made in brain and can be induced by IL-1beta in astrocytes and microglia. We find that COX-2 inhibitors influence astrocyte gene responses. Interestingly, treatment of cells with COX-1 selective inhibitors shows similar effects. Moreover, we find that IL-1beta up-regulates multiple components of the PGE2 synthesizing and responsive pathway in cultured astrocytes, including two recently described PGE synthases and at least one PGE receptor. These molecules are in turn influenced by COX inhibition. Finally, we find many of the same effects in vivo using direct IL-1 beta injection. Based on these results we now propose that PGE2 synthesis and response systems are modulated at multiple, interdependent levels following stimulation with proinflammatory cytokines, providing a mechanism to shift cells to a new phenotype characterized by altered production of, and responsiveness to, inflammatory mediators. We further postulate that COX-1 activity coupled to cytosolic PGE synthase (cPGES) is required as a first phase for efficient PGE2 synthesis in cultured astrocytes and in brain. To examine these hypotheses, we will characterize the regulation of PGE2 synthetic pathways by IL-1beta, focusing on an apparent dependence for COX-1 and cPGES. In the second aim, we will investigate the influence of IL-1a on cell and tissue responses to PGE2, initially focusing on regulation and actions of the EP2 subtype of PGE2 receptor.
In aim three, we will employ long-term ICV infusion of IL-1beta and transgenic mutant APP mice (Tg2576) to establish whether changes observed in our acute paradigms are relevant in chronic neuroinflammation. Together, these studies examine the role of PGE2 in acute and chronic CNS inflammation. This work will provide a clearer understanding of the mechanisms by which anti-inflammatory drugs influence AD, and may reveal new avenues for therapeutic intervention. Moreover, these studies have relevance to pathological processes occurring in head trauma, stroke, and other neurodegenerative diseases where glial activation and inflammation-related changes take place.
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