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The Journal of Neuroscience, March 17, 2004, 24(11):2837-2845; doi:10.1523/JNEUROSCI.4789-03.2004

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Cellular/Molecular
Interleukin-1 Induces a Reactive Astroglial Phenotype via Deactivation of the Rho GTPase–Rock Axis

Gareth R. John,^1,2 Lanfen Chen,² Mark A. Rivieccio,² Carmen V. Melendez-Vasquez,⁴ Adam Hartley,³ and Celia F. Brosnan^2,3

¹Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, Departments of ²Pathology and ³Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and ⁴Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016

The cytokine interleukin-1 (IL-1) is critical to the formation of an astrocytic scar after CNS injury, but the mechanisms by which it induces a reactive phenotype remain unresolved. Here, we show that IL-1 regulates the phenotype of astrocytes via deactivation of the Rho GTPase–Rho kinase (ROCK) pathway, which governs cellular morphology and migration via effects on F-actin and its interactions with focal adhesions, nonmuscle myosin, and microvillar adapter proteins of the ezrin–radixin–moesin (ERM) family. We found that IL-1 induced cortical reorganization of F-actin and dephosphorylation of focal adhesion kinase, myosin light chain 2, and myosin phosphatase targeting subunit 1 in primary human astrocytes, and that all of these effects were mimicked by Rho-ROCK pathway blockade. We also found that IL-1 conversely potentiated ERM phosphorylation, and that this effect was mediated via a Rho–ROCK-independent mechanism. Next, we used a rhotekin pulldown assay to confirm directly that IL-1 deactivates Rho, and further demonstrated that a constitutively active Rho construct rescued astrocytes from developing an IL-1-induced reactive phenotype. These data implicate cytokine regulation of the Rho–ROCK pathway in the generation of a reactive astrogliosis, and we suggest that interventions targeted at this level may facilitate manipulation of the glial scar in inflammatory disorders of the human CNS.

Key words: astrocyte; inflammation; interleukin; myosin; focal adhesions; RhoA

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Received Oct 23, 2003; revised January 21, 2004; accepted January 23, 2004.

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