RETRACTED: SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis.
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.
Puneet
Padmam
P
Department of Physiology, National University of Singapore, 117597 Singapore.
Yap
Celestial T
CT
Wong
Lingkai
L
Lam
Yulin
Y
Koh
Dow Rhoon
DR
Moochhala
Shabbir
S
Pfeilschifter
Josef
J
Huwiler
Andrea
A
Melendez
Alirio J
AJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004731:Endotoxins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D010538:Peritonitis / Q000201:enzymology / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D034622:RNA Interference; D018805:Sepsis / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D012772:Shock, Septic / Q000201:enzymology / Q000276:immunology*; D015398:Signal Transduction; D015854:Up-Regulation; D055815:Young Adult; D000099157:Sphingosine Kinase
D001426:Bacterial Proteins; D016207:Cytokines; D004731:Endotoxins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008074:Lipoproteins; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D051745:Protein Kinase C-delta; D000099157:Sphingosine Kinase