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J. Biol. Chem., Vol. 280, Issue 14, 13742-13751, April 8, 2005

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A Novel Role of Lactosylceramide in the Regulation of Tumor Necrosis Factor -mediated Proliferation of Rat Primary Astrocytes

IMPLICATIONS FOR ASTROGLIOSIS FOLLOWING NEUROTRAUMA^*

Ravinder Pannu, Avtar K. Singh, and Inderjit Singh¶

From the Department of Pediatrics, Department of Pathology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina and Medical University of South Carolina, Charleston, South Carolina 29425

The present study describes the role of glycosphingolipids in neuroinflammatory disease and investigates tumor necrosis factor (TNF)-induced astrogliosis following spinal cord injury. Astrogliosis is the hallmark of neuroinflammation and is characterized by proliferation of astrocytes and increased glial fibrillary acidic protein (GFAP) gene expression. In primary astrocytes, TNF stimulation increased the intracellular levels of lactosylceramide (LacCer) and induced GFAP expression and astrocyte proliferation. D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol·HCl (PDMP), a glucosylceramide synthase and LacCer synthase (GalT-2) inhibitor, inhibited astrocyte proliferation and GFAP expression, which were reversed by exogenous supplementation of LacCer but not by other glycosphingolipids. TNF caused a rapid increase in the activity of GalT-2 and synthesis of LacCer. Silencing of GalT-2 gene using antisense oligonucleotides also attenuated the proliferation of astrocytes and GFAP expression. The PDMP and antisense-mediated inhibition of proliferation and GFAP expression was well correlated with decreased Ras/ERK1/2 pathway activation. Furthermore, TNF-mediated astrocyte proliferation and GFAP expression was also inhibited by LY294002, a phosphatidylinositol 3-kinase inhibitor, which was reversed by exogenous LacCer. LY294002 also inhibited TNF-induced GalT-2 activation and LacCer synthesis, suggesting a phosphatidylinositol 3-kinase-mediated regulation of GalT-2. In vivo, PDMP treatment attenuated chronic ERK1/2 activation and spinal cord injury (SCI)-induced astrocyte proliferation with improved functional recovery post-SCI. Therefore, the in vivo studies support the conclusions drawn from cell culture studies and provide evidence for the role of LacCer in TNF-induced astrogliosis in a rat model of SCI. To our knowledge, this is the first report demonstrating the role of LacCer in the regulation of TNF-induced proliferation and reactivity of primary astrocytes.

Received for publication, October 21, 2004 , and in revised form, January 18, 2005.

^* This study was supported in part by National Institutes of Health Grants NS-22576, NS-34741, NS-40144, and NS-37766. 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.

^¶ To whom correspondence should be addressed: Dept. of Pediatrics, Medical University of South Carolina, 316 Clinical Science Bldg., 96 Jonathan Lucas St., Charleston, SC 29425. Tel.: 843-792-7542; Fax: 843-792-7130; E-mail: singhi{at}musc.edu.

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