IL-18 time-dependently modulates Th1/Th2 cytokine production by ligand-activated NKT cells.
While IL-18 synergizes with IL-12 to induce a Th1 immune response, it also promotes a Th2 response. Here we investigate the modulatory role of IL-18 on the Th1/Th2 cytokine response. The injection of alpha-galactosylceramide (alpha-GalCer), a ligand for NKT cells, elevated mouse serum levels of both IFN-gamma and IL-4. When the mice were treated 2 h before alpha-GalCer challenge with IL-18, IFN-gamma production but not IL-4 production was remarkably up-regulated. In contrast, pretreatment with IL-18 6 h before the challenge enhanced IL-4 production. However, this IL-18-enhanced IL-4 production was not elicited in mice injected with anti-CD3 Ab. Liver mononuclear cells (MNC) produced a similar cytokine production pattern when MNC from mice treated with IL-18 either 2 h or 6 h before challenge were stimulated with alpha-GalCer in vitro. Expression of SOCS1 and SOCS3 was notably up-regulated in the liver MNC from mice pretreated 6 h before with IL-18; in particular, SOCS3 expression was confined to the liver NKT cells. Inhibition of SOCS3 by RNA interference up-regulated the phosphorylation of STAT3 and suppressed in vitro IL-4 production by IL-18-primed liver MNC stimulated with alpha-GalCer, but it did not affect IFN-gamma production. These results suggest that IL-18 time-dependently modulates Th1/Th2 cytokine production in ligand-activated NKT cells by regulating/inducing SOCS3 expression.
Uchida
Takefumi
T
Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan.
Kinoshita
Manabu
M
Fukasawa
Masashi
M
Habu
Yoshiko
Y
Shinomiya
Nariyoshi
N
Seki
Shuhji
S
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000145:classification; D005699:Galactosylceramides / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000008:administration & dosage / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D005699:Galactosylceramides; D020382:Interleukin-18; D008024:Ligands; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D007371:Interferon-gamma