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Molecular and Cellular Biology, September 2004, p. 7359-7369, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7359-7369.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Sphingosine Kinase Protects Lipopolysaccharide-Activated Macrophages from Apoptosis

Weicheng Wu, Raymond D. Mosteller, and Daniel Broek*

Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine at the University of Southern California, Los Angeles, California 90089

Received 2 October 2003/ Returned for modification 13 November 2003/ Accepted 28 May 2004

Lipopolysaccharide (LPS) signaling is critical for the innate immune response to gram-negative bacteria. Here, evidence is presented for LPS stimulation of sphingosine kinase (SPK) in the RAW 264.7 murine macrophage cell line and rat primary hepatic macrophages (HMs). LPS treatment of RAW 264.7 cells resulted in a time- and dose-dependent activation of SPK and membrane translocation of SPK1. Further, LPS-induced SPK activation was blocked by SPK1-specific small interfering RNA (siRNA). Overexpression of Toll-like receptor 4 and MD2, the receptor and coreceptor of LPS, in HEK 293 cells activated SPK activity in the absence of LPS treatment. Inhibition of SPK by the pharmacological inhibitor N,N-dimethylsphingosine (DMS) or SPK1-specific siRNA blocked LPS stimulation of extracellular signal-regulated kinase 1/2 and p38 but enhanced LPS-induced c-Jun N-terminal kinase activation. The SPK inhibitor DMS and dominant-negative SPK1 also blocked LPS activation of Elk-1 and NF-{kappa}B reporters in RAW 264.7 cells. Inhibition of SPK sensitized RAW 264.7 cells and HMs to LPS-induced apoptosis. These data demonstrate the critical role of SPK1 in LPS signaling in macrophages and suggest that SPK1 is a potential therapeutic target to block hyperimmune responses induced by gram-negative bacteria.

* Corresponding author. Mailing address: Norris Comprehensive Cancer Center, Room 5322, University of Southern California, 1441 Eastlake Ave., Los Angeles, CA 90089. Phone: (323) 865-0523. Fax: (323) 865-0154. E-mail: broek{at}usc.edu.

Molecular and Cellular Biology, September 2004, p. 7359-7369, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7359-7369.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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