Sphingosine kinase 1 regulates pro-inflammatory responses triggered by TNFalpha in primary human monocytes.
Monocytes play an important role in inflammation, angiogenesis, and atherosclerosis. During these processes monocytes release pre-formed proinflammatory mediators from granules, and synthesize de novo cytokines and chemokines important in the amplification of the inflammatory response. One of the most prominent triggers of inflammatory responses is the cytokine TNFalpha. However, the intracellular signaling cascades triggered by TNFalpha are not fully understood. In this study we investigated the roles of SPHK on the TNFalpha-triggered responses on human primary monocytes. We show that TNFalpha rapidly triggers S1P generation and activation of SPHK. Moreover, our data shows that SPHK1 is the isoform activated by TNFalpha, and plays an essential role on the TNFalpha-triggered intracellular Ca2+ signals, degranulation, cytokine production, and activation of NFkappaB, thus suggesting a pivotal role for SPHK1 on the proinflammatory responses triggered by TNFalpha.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Liang
L
Zhi
Bernard P
BP
Leung
Alirio J
AJ
Melendez
D015153:Blotting, Western; D002118:Calcium / Q000032:analysis / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology*; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics / Q000502:physiology; D008246:Lysophospholipids / Q000032:analysis / Q000378:metabolism; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000097782:NF-kappaB-Inducing Kinase; D000099157:Sphingosine Kinase
D002118:Calcium; D016207:Cytokines; D007527:Isoenzymes; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate