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Science 328 (5983): 1290-1294

Copyright © 2010 by the American Association for the Advancement of Science

SphK1 Regulates Proinflammatory Responses Associated with Endotoxin and Polymicrobial Sepsis

Padmam Puneet,1 Celestial T. Yap,1 Lingkai Wong,2 Lam Yulin,2 Dow Rhoon Koh,1 Shabbir Moochhala,3 Josef Pfeilschifter,4 Andrea Huwiler,5 Alirio J. Melendez1,6,*

Abstract: During sepsis, activation of phagocytes leads to the overproduction of proinflammatory cytokines, causing systemic inflammation. Despite substantial information regarding the underlying molecular mechanisms that lead to sepsis, several elements in the pathway remain to be elucidated. We found that the enzyme sphingosine kinase 1 (SphK1) is up-regulated in stimulated human phagocytes and in peritoneal phagocytes of patients with severe sepsis. Blockade of SphK1 inhibited phagocyte production of endotoxin-induced proinflammatory cytokines. We observed protection against sepsis in mice treated with a specific SphK1 inhibitor that was enhanced by treatment with a broad-spectrum antibiotic. These results demonstrated a critical role for SphK1 in endotoxin signaling and sepsis-induced inflammatory responses and suggest that inhibition of SphK1 is a potential therapy for septic shock.

1 Department of Physiology, National University of Singapore, 117597 Singapore.
2 Department of Chemistry, National University of Singapore, 117543 Singapore.
3 Defence Medical and Environmental Research Institute, DSO National Laboratories, 117510 Singapore.
4 Pharmazentrum Frankfurt, University Hospital, Frankfurt am Main 60590, Germany.
5 Institute of Pharmacology, University of Bern, Bern CH-3010, Switzerland.
6 Medicine-Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, Scotland, UK.

* To whom correspondence should be addressed. E-mail: a.melendez-romero{at}clinmed.gla.ac.uk


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