IL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells.
The canonical pathway for IL-1β production requires TLR-mediated NF-κB-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1β. Here we show that IL-21 unexpectedly induces IL-1β production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-κB-independent pathway. IL-21 does not induce Il1b expression in CD4(+) T cells, with differential histone marks present in these cells versus cDCs. IL-21-induced IL-1β processing in cDCs does not require caspase-1 or caspase-8 but depends on IL-21-mediated death and activation of serine protease(s). Moreover, STAT3-dependent IL-1β expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with pneumonia virus of mice. These results demonstrate lineage-restricted IL-21-induced IL-1β via a non-canonical pathway and provide evidence for its importance in vivo.
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B05, Bethesda, Maryland 20892-1674 USA.
Chi-Keung
CK
Wan
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B05, Bethesda, Maryland 20892-1674 USA.
Peng
P
Li
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B05, Bethesda, Maryland 20892-1674 USA.
Rosanne
R
Spolski
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B05, Bethesda, Maryland 20892-1674 USA.
Jangsuk
J
Oh
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B05, Bethesda, Maryland 20892-1674 USA.
Allison B
AB
Andraski
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B05, Bethesda, Maryland 20892-1674 USA.
Ning
N
Du
Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 6D19, Bethesda, Maryland, 20892-1674 USA.
Zu-Xi
ZX
Yu
Department of Immunology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105 USA.
Christopher P
CP
Dillon
Department of Immunology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105 USA.
Douglas R
DR
Green
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B05, Bethesda, Maryland 20892-1674 USA.
Warren J
WJ
Leonard
D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism; D001854:Bone Marrow Cells; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D000098546:Interleukin-21
D018949:Antigens, CD1; C437944:CD1C protein, human; D006023:Glycoproteins; D053583:Interleukin-1beta; D007378:Interleukins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D000098546:Interleukin-21