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      Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury

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          Abstract

          In the central nervous system (CNS), the transcription factor nuclear factor (NF)- κB is a key regulator of inflammation and secondary injury processes. After trauma or disease, the expression of NF- κB–dependent genes is highly activated, leading to both protective and detrimental effects on CNS recovery. We demonstrate that selective inactivation of astroglial NF- κB in transgenic mice expressing a dominant negative (dn) form of the inhibitor of κB α under the control of an astrocyte-specific promoter (glial fibrillary acidic protein [GFAP]–dn mice) leads to a dramatic improvement in functional recovery 8 wk after contusive spinal cord injury (SCI). Histologically, GFAP mice exhibit reduced lesion volume and substantially increased white matter preservation. In parallel, they show reduced expression of proinflammatory chemokines and cytokines, such as CXCL10, CCL2, and transforming growth factor– β2, and of chondroitin sulfate proteoglycans participating in the formation of the glial scar. We conclude that selective inhibition of NF- κB signaling in astrocytes results in protective effects after SCI and propose the NF- κB pathway as a possible new target for the development of therapeutic strategies for the treatment of SCI.

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          Most cited references 51

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          An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.

          Studies on mice deficient in nuclear factor kappa B (NF-kappaB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-alpha (TNF-alpha)-dependent genes. Treatment of RelA-deficient (RelA-/-) mouse fibroblasts and macrophages with TNF-alpha resulted in a significant reduction in viability, whereas RelA+/+ cells were unaffected. Cytotoxicity to both cell types was mediated by TNF receptor 1. Reintroduction of RelA into RelA-/- fibroblasts resulted in enhanced survival, demonstrating that the presence of RelA is required for protection from TNF-alpha. These results have implications for the treatment of inflammatory and proliferative diseases.
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            Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation.

            Nuclear factor-kappaB (NF-kappaB) is a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis. Activation of NF-kappaB mainly occurs via IkappaB kinase (IKK)-mediated phosphorylation of inhibitory molecules, including IkappaBalpha. Optimal induction of NF-kappaB target genes also requires phosphorylation of NF-kappaB proteins, such as p65, within their transactivation domain by a variety of kinases in response to distinct stimuli. Whether, and how, phosphorylation modulates the function of other NF-kappaB and IkappaB proteins, such as B-cell lymphoma 3, remains unclear. The identification and characterization of all the kinases known to phosphorylate NF-kappaB and IkappaB proteins are described here. Because deregulation of NF-kappaB and IkappaB phosphorylations is a hallmark of chronic inflammatory diseases and cancer, newly designed drugs targeting these constitutively activated signalling pathways represent promising therapeutic tools.
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              Reactive astrocytes: cellular and molecular cues to biological function.

              For several decades, the reactive gliosis that occurs after an injury to the CNS has been considered one of the major impediments to axonal regeneration. Nevertheless, recent studies have suggested that in certain conditions, reactive astrocytes may provide a permissive substratum to support axonal regrowth. The important criteria, allowing for the distinction between permissive and non-permissive gliosis, are the ultrastructural 3D organization of the scar and more importantly the recognition molecules expressed by reactive astrocytes. Reactive astrocytes express surface molecules and produce various neurotrophic factors and cytokines. The latter in turn might modulate the production of recognition molecules by reactive astrocytes, allowing them to support post-lesional axonal regrowth. Although numerous recent articles have focused on cytokines and cell adhesion molecules, scant attention has been paid to reactive astrocytes. Reactive astrocytes should be considered a key element, like neurons, of a dynamic environment, thus forming with neurons a functional unit involved in homeostasis, plasticity and neurotransmission. Attempts are in progress to identify molecular markers for reactive astrocytes.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                4 July 2005
                : 202
                : 1
                : 145-156
                Affiliations
                [1 ]The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136
                [2 ]Neuroscience Program, Miller School of Medicine, University of Miami, Miami, FL 33136
                [3 ]Department of Psychology, University of Miami, Miami, FL 33124
                Author notes

                CORRESPONDENCE John R. Bethea: JBethea@ 123456miami.edu OR Roberta Brambilla: r.brambilla@ 123456miami.edu

                Article
                20041918
                10.1084/jem.20041918
                2212896
                15998793
                Copyright © 2005, The Rockefeller University Press
                Categories
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                Medicine

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