Early target genes of IL-12 and STAT4 signaling in th cells.
IL-12 signaling through STAT4 is essential for induction of optimal levels of IFN-gamma production and commitment of Th1 cells. The molecular mechanism that controls how IL-12 and STAT4 signaling induces Th1 differentiation is poorly described. To identify the early target genes of IL-12 and STAT4 signaling, oligonucleotide arrays were used to compare the gene expression profiles of wild-type and STAT4-knockout murine Th cells during the early Th1 differentiation. According to the results, 20 genes were regulated in an IL-12- and STAT4-dependent manner. Importantly, Ifngamma was clearly the first gene induced by IL-12 in a STAT4-dependent manner. Most of the other defects in gene expression in STAT4-knockout cells were seen after 48 h of Th1 polarization. In addition to IL-12 signaling mediated by STAT4, STAT4-independent induction of a number of genes was observed immediately in response to Th1 induction. This induction was at least in part driven by IFN-gamma independently of STAT4. Importantly, addition of exogenous IFN-gamma into Th1 cell cultures of STAT4-knockout cells restored the defect in IFN-gamma production further demonstrating the critical role of IFN-gamma in early Th1 differentiation.
Lund
Riikka J
RJ
Turku Centre for Biotechnology, Turku University and Abo Akademi, Turku Graduate School of Biomedical Sciences, Turku University, Turku, Finland. riikka.lund@btk.utu.fi
Chen
Zhi
Z
Scheinin
Joonas
J
Lahesmaa
Riitta
R
D000818:Animals; D002454:Cell Differentiation; D016764:Cell Polarity; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D018417:Th1 Cells / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma