The astrocyte, the major glial cell of the central nervous system (CNS), performs a wide variety of critical functions in the CNS. They include: 1) contributing to the structural integrity of the blood-brain barrier (BBB), 2) responding to CNS infection or trauma, and 3) performing as an immunocompetent cell within the CNS. In particular, the astrocyte can respond to and/or secrete a variety of cytokines. We have shown that astrocytes secrete interleukin-6 (IL-6) in response to the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interferon- gamma (IFN-gamma). These cytokines induce IL-6 production by acting both independently and synergistically. IL-6 is a pleiotropic cytokine involved in both inflammatory and immunological responses. We propose that cytokine-induced astrocyte IL-6 production is involved in mediating heightened immunological and inflammatory reactions associated with neurologic diseases such as multiple sclerosis (MS), AIDS dementia complex and experimental allergic encephalomyelitis (EAE). The multiple effects of IL-6 on various cell populations in the CNS, including autocrine stimulation of astrocytes, suggests that IL-6 has a central role in augmenting infiltration of inflammatory cells, gliosis, and intracerebral humoral immune responses, all pathogenic mechanisms involved in immune- mediated CNS disorders. As such, it is critical to first understand the basic biological mechanisms underlying induction and regulation of astrocyte IL-6 production. We will examine in detail the induction of IL-6 genes by TNF-alpha and IL-1Beta by analysis of transcription rates, steady-state mRNA levels, mRNA stability, and IL-6 protein expression. We will also investigate the intracellular mechanisms of action of TNF-alpha and IL-1Beta by examining the role of protein kinase C (PKC) and cyclic AMP (cAMP) second messenger systems in astrocyte IL-6 expression. The molecular mechanisms underlying IL-6 gene expression by astrocytes in response to TNF-alpha and IL-1Beta will be studied by examining the IL-6 DNA regulatory elements and nuclear factors utilized by cytokine-stimulated astrocytes. The two cytokines, TNF-alpha and IL-1Beta, may play a pivotal role in the induction of IL-6 production by astrocytes. The studies described in this proposal will contribute to understanding the basic cellular and molecular responses of the astrocyte to TNF-alpha and IL-1Beta. Local CNS production of IL-6 by resident astroglial cells in response to these cytokines may contribute to the pathogenesis of inflammatory demyelinating diseases, particularly with regard to B-cell differentiation and immunoglobulin secretion within the CNS.
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