IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production.
Interleukin-12 (IL-12) and IL-18 induce synergistic transcription of interferon gamma (IFN-gamma) that is T cell receptor (TCR)-independent, not inhibited by cyclosporin A and requires new protein synthesis. To characterize this pathway, we screened for genes that are induced in IL-12- and IL-18-treated T helper type 1 cells. GADD45 beta, which activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase kinase 4 (MEKK4), was induced by IL-18 and augmented by IL-12. GADD45 beta expression in naïve CD4+ T cells activated p38 MAPK and selectively increased cytokine-induced, but not TCR-induced, IFN-gamma production. Kinase-inactive MEKK4 and inhibition of the p38 MAPK pathway both selectively inhibit cytokine-induced, but not TCR-induced, IFN-gamma production. Thus, the synergy between IL-12 and IL-18 may involve GADD45 beta induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-gamma production.
Yang
J
J
Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA.
Zhu
H
H
Murphy
T L
TL
Ouyang
W
W
Murphy
K M
KM
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins
D016207:Cytokines; D017931:DNA Primers; D007371:Interferon-gamma; D018664:Interleukin-12; D020382:Interleukin-18; D047908:Intracellular Signaling Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins; C482779:MAP3K4 protein, human; C482780:Map3k4 protein, mouse