Sphingosine kinase inhibitor suppresses IL-18-induced interferon-gamma production through inhibition of p38 MAPK activation in human NK cells.
Natural killer (NK) cells play an important role in the innate immune response. Interleukin-18 (IL-18) is a well-known interferon-gamma (IFN-gamma inducing factor, which stimulates immune response in NK and T cells. Sphingosine kinase (SPHK) catalyzes the formation of sphingosine 1-phosphate (S1P), which acts as a second messenger to function as an anti-apoptotic factor and proliferation stimulator of immune cells. In this study, to elucidate whether SPHK is involved in IL-18-induced IFN-gamma production, we measured IL-18-induced IFN-gamma production after pre-treatment with SPHK inhibitor (SKI) in NK-92MI cells. We found that IL-18-induced IFN-gamma expression was blocked by SKI pre-treatment in both mRNA and protein levels. In addition, the increased IFN-gamma production by stimulation with IL-18 is mediated through both SPHK and p38 MAPK. To determine the upstream signals of SKI and p38 MAPK in IL-18-induced IFN-gamma production, phosphorylation levels of p38 MAPK was measured after SKI pre-treatment. As a result, inhibition of SPHK by SKI blocked phosphorylation of p38 MAPK, showing that SPHK activation by IL-18 is an upstream signal of p38 MAPK activation. Inhibition of SPHK by SKI also inhibited IL-18-induced IFN-gamma production in human primary NK cells. In conclusion, SPHK activation is an essential factor for IL-18-induced IFN-gamma production via p38 MAPK.
Cheon
Soyoung
S
Department of Life Science, Sookmyung Women's University, Hyochangwon-gil 52, Seoul 140-742, Republic of Korea.
Song
Seok Bean
SB
Jung
Minkyung
M
Park
Yoorim
Y
Bang
Jung-Wook
JW
Kim
Tae Sung
TS
Park
Hyunjeong
H
Kim
Cherl-Hyun
CH
Yang
Yool-Hee
YH
Bang
Sa Ik
SI
Cho
Daeho
D
D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020382:Interleukin-18 / Q000494:pharmacology / Q000502:physiology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008246:Lysophospholipids / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000099157:Sphingosine Kinase
D007371:Interferon-gamma; D020382:Interleukin-18; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D013110:Sphingosine; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate