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J. Biol. Chem., Vol. 279, Issue 8, 6688-6695, February 20, 2004

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Caveolin-1 Knockdown by Small Interfering RNA Suppresses Responses to the Chemokine Monocyte Chemoattractant Protein-1 by Human Astrocytes^*

Shujun Ge and Joel S. Pachter

From the Blood-Brain Barrier Laboratory, Department of Pharmacology, University of Connecticut Health Center, Farmington, Connecticut 06030

Astrocytes regulate the integrity of the blood-brain barrier and influence inflammatory processes in the central nervous system. The pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1), which is both released by and stimulates astrocytes, is thought to play a crucial role in both these activities. Because astrocytes have been shown to possess caveolae, vesicular structures that participate in intracellular transport and signal transduction events, we reasoned that expression of the major structural protein of these organelles, caveolin-1, might feature critically in the cellular responses to MCP-1. To test this hypothesis, caveolin-1 level was "knocked down" in human astrocyte cultures by using a small interfering RNA approach. This method resulted in efficient (>90% loss) and specific knockdown of caveolin-1 expression while sparring glial fibrillary acidic protein as well as several other proteins involved in endocytosis. Astrocytes suffering caveolin-1 loss showed diminished ability to down-modulate and internalize the MCP-1 receptor (CCR2) in response to exposure to this chemokine and also demonstrated significantly reduced capacity to undergo chemotaxis and calcium flux when MCP-1-stimulated. The results highlight a potentially prominent role for caveolae and/or caveolin-1 in mediating astrocyte responses to MCP-1, a feature that might significantly dictate the progression of inflammatory events at the blood-brain barrier.

Received for publication, October 27, 2003 , and in revised form, December 4, 2003.

^* This work was supported by National Institutes of Health Grant RO-1-MH54718 and National Multiple Sclerosis Society Grant R G2633 (to J. S. P.). 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 Pharmacology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030. Tel.: 860-679-3698; Fax: 860-679-3693; E-mail: pachter{at}nso1.uchc.edu.

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