A critical role for sphingosine kinase in anaphylatoxin-induced neutropenia, peritonitis, and cytokine production in vivo.
The aim of our study was to investigate the roles played by sphingosine kinase (SPHK) in the anaphylatoxin C5a-triggered responses in vivo. Our data show that i.v. administration of C5a triggers a rapid neutropenic response, but pretreating mice with the SPHK inhibitor, N,N-dimethylsphingosine (DMS), 10 min before the C5a i.v. administration substantially inhibited the C5a-triggered neutropenia. Similarly the i.v. administration of C5a caused a rapid increase in the serum levels of TNF-alpha and IL-6, and this increase in cytokine levels was blocked by DMS. We then induced acute peritonitis with C5a. The C5a i.p. injection triggered a fast recruitment of neutrophils, later followed by monocytes, into the peritoneal cavity. Vascular permeability was also observed: when we i.v. injected Evans blue before C5a i.p. injection, we could observe a continued influx of the dye into the peritoneum. In mice pretreated with DMS, there was a significant reduction on the C5a-triggered neutrophil and monocyte infiltration, as well as a marked reduction on the Evans blue influx. Our data also show that the i.p. administration of C5a caused a rapid increase in TNF-alpha and IL-6 levels in the peritoneal cavity, and this increase in cytokine levels was substantially inhibited in mice pretreated with the SPHK inhibitor. Taken together, these observations suggest a potential role for SPHK in the C5a-triggered inflammatory responses in vivo.
Vlasenko
Liudmila Pietrovna
LP
Department of Physiology, National University of Singapore, Singapore. phsmraj@nus.edu.sg
Melendez
Alirio J
AJ
D000818:Animals; D002199:Capillary Permeability / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015936:Complement C5a / Q000008:administration & dosage*; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D009503:Neutropenia / Q000201:enzymology* / Q000276:immunology* / Q000517:prevention & control; D020556:Neutrophil Infiltration / Q000276:immunology; D010529:Peritoneal Cavity / Q000473:pathology; D010533:Peritoneal Lavage; D010538:Peritonitis / Q000201:enzymology* / Q000276:immunology* / Q000517:prevention & control; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D000099157:Sphingosine Kinase
D015936:Complement C5a; D016207:Cytokines; D015850:Interleukin-6; D017853:Phosphotransferases (Alcohol Group Acceptor); D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase