IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells.
IFN-alpha and IL-12 are macrophage-derived cytokines that enhance innate and Th1 immune responses. However, there is little information regarding IFN-alpha and IL-12 target genes that would be involved in mediating the immunostimulatory effects of these cytokines. The interferon regulatory factor (IRF) family of transcription factors is known to be involved in controlling lymphocyte differentiation and functions. In this work we have studied the effect of IFN-alpha and IL-12 on the expression of IRF transcription factors in human NK and T cells. Both IFN-alpha and IL-12 strongly up-regulated IRF-1, IRF-4, and IRF-8 mRNA and protein expression. The binding of IRF-4 and IRF-8 to the lambdaB gene enhancer sequence was also increased following IFN-alpha- and IL-12-treatment of NK and T cells. A GAS element from the promoter region of the IRF-4 gene was identified. Following stimulation of cells with IFN-alpha or IL-12, Stat4 was found to bind to this IRF-4 GAS element, as detected by EMSA and DNA affinity binding, implying that the IRF-4 gene is directly activated by both cytokines. Our results suggest that IFN-alpha and IL-12 may enhance innate and Th1 immune responses by inducing IRF-1, IRF-4, and IRF-8 gene expression.
Department of Microbiology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. anne.lehtonen@ktl.fi
Anne
A
Lehtonen
Riikka
R
Lund
Riitta
R
Lahesmaa
Ilkka
I
Julkunen
Timo
T
Sareneva
Sampsa
S
Matikainen
D001665:Binding Sites; D016764:Cell Polarity; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D050797:STAT4 Transcription Factor; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D018664:Interleukin-12; D010750:Phosphoproteins; D012097:Repressor Proteins; D050797:STAT4 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C494257:IRF1 protein, human; C494090:STAT4 protein, human