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J. Biol. Chem., Vol. 283, Issue 32, 21953-21964, August 8, 2008

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Interleukin-1β-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity^*

Michelle A. Sama¹, Diana M. Mathis¹, Jennifer L. Furman, Hafiz Mohmmad Abdul^¶, Irina A. Artiushin^¶, Susan D. Kraner, and Christopher M. Norris^¶2

From the Department of Molecular and Biomedical Pharmacology, Graduate Center for Gerontology, and the ^¶Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536

Interleukin-1β (IL-1β) and the Ca²⁺/calmodulin-dependent protein phosphatase, calcineurin, have each been shown to play an important role in neuroinflammation. However, whether these signaling molecules interact to coordinate immune/inflammatory processes and neurodegeneration has not been investigated. Here, we show that exogenous application of IL-1β (10 ng/ml) recruited calcineurin/NFAT (nuclear factor of activated T cells) activation in primary astrocyte-enriched cultures within minutes, through a pathway involving IL-1 receptors and L-type Ca²⁺ channels. Adenovirus-mediated delivery of the NFAT inhibitor, VIVIT, suppressed the IL-1β-dependent induction of several inflammatory mediators and/or markers of astrocyte activation, including tumor necrosis factor , granulocyte/macrophage colony-stimulating factor, and vimentin. Expression of an activated form of calcineurin in one set of astrocyte cultures also triggered the release of factors that, in turn, stimulated NFAT activity in a second set of "naive" astrocytes. This effect was prevented when calcineurin-expressing cultures co-expressed VIVIT, suggesting that the calcineurin/NFAT pathway coordinates positive feedback signaling between astrocytes. In the presence of astrocytes and neurons, 48-h delivery of IL-1β was associated with several excitotoxic effects, including NMDA receptor-dependent neuronal death, elevated extracellular glutamate, and hyperexcitable synaptic activity. Each of these effects were reversed or ameliorated by targeted delivery of VIVIT to astrocytes. IL-1β also caused an NFAT-dependent reduction in excitatory amino acid transporter levels, indicating a possible mechanism for IL-1β-mediated excitotoxicity. Taken together, the results have potentially important implications for the propagation and maintenance of neuroinflammatory signaling processes associated with many neurodegenerative conditions and diseases.

Received for publication, January 7, 2008 , and in revised form, June 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AG 027297, AG 024190, RR020171, AR046477, and AG010836. Portions of this work have been published in abstract form (37–39). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: 131 Sanders-Brown Bldg., 800 South Limestone St., University of Kentucky College of Medicine, Lexington, KY 40536. Fax: 859-323-2866; E-mail: cnorr2{at}uky.edu.

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