Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES induction through p38 mitogen-activated protein kinase but independently of nuclear factor κB activation.
Sphingosine kinase 1 (SK1) produces the pro-survival sphingolipid sphingosine 1-phosphate and has been implicated in inflammation, proliferation, and angiogenesis. Recent studies identified TRAF2 as a sphingosine 1-phosphate target, implicating SK1 in activation of the NF-κB pathway, but the functional consequences of this connection on gene expression are unknown. Here, we find that loss of SK1 potentiates induction of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted; also known as CCL5) in HeLa cells stimulated with TNF-α despite RANTES induction being highly dependent on the NF-κB pathway. Additionally, we find that SK1 is not required for TNF-induced IKK phosphorylation, IκB degradation, nuclear translocation of NF-κB subunits, and transcriptional NF-κB activity. In contrast, loss of SK1 prevented TNF-induced phosphorylation of p38 MAPK, and inhibition of p38 MAPK, like SK1 knockdown, also potentiates RANTES induction. Finally, in addition to RANTES, loss of SK1 also potentiated the induction of multiple chemokines and cytokines in the TNF response. Taken together, these data identify a potential and novel anti-inflammatory function of SK1 in which chemokine levels are suppressed through SK1-mediated activation of p38 MAPK. Furthermore, in this system, activation of NF-κB is dissociated from SK1, suggesting that the interaction between these pathways may be more complex than currently thought.
Department of Medicine, Stony Brook University, Stony Brook, New York 11794.
Mohamad M
MM
Adada
Department of Pathology, Microbiology and Immunology, University of South Carolina, School of Medicine, Columbia, South Carolina 29209.
K Alexa
KA
Orr-Gandy
Department of Medicine, Stony Brook University, Stony Brook, New York 11794; Northport Veterans Affairs Medical Center, Northport, New York 11768.
Ashley J
AJ
Snider
Department of Medicine, Stony Brook University, Stony Brook, New York 11794.
Daniel
D
Canals
Department of Medicine, Stony Brook University, Stony Brook, New York 11794.
Yusuf A
YA
Hannun
Department of Medicine, Stony Brook University, Stony Brook, New York 11794; Northport Veterans Affairs Medical Center, Northport, New York 11768. Electronic address: lina.obeid@stonybrookmedicine.edu.
Lina M
LM
Obeid
Department of Medicine, Stony Brook University, Stony Brook, New York 11794.
Christopher J
CJ
Clarke
D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000099157:Sphingosine Kinase
D018946:Chemokine CCL5; D051550:I-kappa B Kinase; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C483024:CCL5 protein, human; C503460:Ccl5 protein, mouse
Chemokines; Inflammation; NF-kappa B (NF-KB); RANTES; Sphingosine Kinase; Sphingosine-1-phosphate; Tumor Necrosis Factor (TNF); p38 MAPK