SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis

Puneet, Padmam; Yap, Celestial T; Wong, Lingkai; Lam, Yulin; Koh, Dow Rhoon; Moochhala, Shabbir; Pfeilschifter, Josef; Huwiler, Andrea; Melendez, Alirio J (2010). SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis. Science, 328(5983), pp. 1290-4. Washington, D.C.: American Association for the Advancement of Science 10.1126/science.1188635

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
UniBE Contributor:	Huwiler, Andrea
ISSN:	0036-8075
Publisher:	American Association for the Advancement of Science
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:09
Last Modified:	05 Dec 2022 14:00
Publisher DOI:	10.1126/science.1188635
PubMed ID:	20522778
Web of Science ID:	000278318600039
URI:	https://boris.unibe.ch/id/eprint/868 (FactScience: 201115)