title: The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells.
abstract: Interleukin-21 (IL-21) has broad actions on T and B cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon-γ (IFN-γ)-producing CD4+ T cells in Il21r(-/-)Rag2(-/-) mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2(-/-) mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response.
authors: Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
authors: Chi-Keung
authors: CK
authors: Wan
authors: Jangsuk
authors: J
authors: Oh
authors: Peng
authors: P
authors: Li
authors: Erin E
authors: EE
authors: West
authors: Elizabeth A
authors: EA
authors: Wong
authors: Allison B
authors: AB
authors: Andraski
authors: Rosanne
authors: R
authors: Spolski
authors: Zu-Xi
authors: ZX
authors: Yu
authors: Jianping
authors: J
authors: He
authors: Brian L
authors: BL
authors: Kelsall
authors: Warren J
authors: WJ
authors: Leonard
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D021901:DNA, Intergenic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D021901:DNA, Intergenic; D004268:DNA-Binding Proteins; D005699:Galactosylceramides; D007378:Interleukins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C499308:Rag2 protein, mouse; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C493154:alpha-galactosylceramide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000098546:Interleukin-21