IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells.
Interleukin (IL)-21 is a T cell-derived cytokine that regulates innate and adaptive immune responses. IL-21 receptor (IL-21R), which is expressed in natural killer (NK) and T cells, is structurally homologous to IL-2Rbeta and IL-15Ralpha. These receptors also share a common cytokine receptor gamma-chain with IL-4, IL-7, and IL-9. Macrophage- or dendritic cell-derived interferon (IFN)-alpha/beta is a key cytokine in regulation of NK and T cell functions. We demonstrate here that in addition to activating IFN-gamma gene expression, IFN-alpha/beta and IL-12 enhance the mRNA expression of IL-21 in activated human T cells. In addition, IFN-alpha/beta enhanced T cell receptor stimulation-induced IL-21 and IFN-gamma gene expression in resting T cells. The promoter analysis of IL-21 gene revealed a putative IFN-gamma activation site element, which was found to bind signal transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4 proteins in IFN-alpha/beta-stimulated NK or T cell extracts. In contrast to IL-21 expression, IFN-alpha/beta down-regulated IL-21R mRNA expression in NK and T cells. IFN-alpha/beta-induced down-regulation of IL-21R expression resulted in reduced STAT3 phosphorylation and DNA binding after IL-21 stimulation. In conclusion, our results suggest a novel role for IFN-alpha/beta in the regulation of IL-21 response.
Strengell
Mari
M
Department of Microbiology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. mari.strengell@ktl.fi
Julkunen
Ilkka
I
Matikainen
Sampsa
S
D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D000098546:Interleukin-21
D004268:DNA-Binding Proteins; C508117:IL21R protein, human; D016898:Interferon-alpha; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D000098546:Interleukin-21