IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype

Huber, Magdalena; Brüstle, Anne; Reinhard, Katharina; Guralnik, Anna; Walter, Gina; Mahiny, Azita Josefine; Löw, Eberhard von; Lohoff, Michael

doi:10.1073/pnas.0809077106

Cited by 256 publications

(215 citation statements)

References 34 publications

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“…IL-21, one of the Th17-associated cytokines that was assessed in the present study, is believed to be of importance for the stabilisation of the Th17 phenotype and for the expression of the transcription factor RORC2 [34,36,37]. In the present study it was found that, as for IL-23, segmental endotoxin exposure increased extracellular concentrations of IL-21 in cell-free BAL samples 12 h after this exposure.…”

Section: Increase In Effector Molecules Downstream Of Il-17 and Il-22supporting

confidence: 61%

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

Glader¹,

Smith²,

Malmhäll³

et al. 2010

Eur Respir J

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Previous studies on mouse models have indicated that interleukin (IL)-17 and IL-17-producing T-helper (Th) cells are important for pulmonary host defence against Gram-negative bacteria. Human correlates to these findings have not yet been demonstrated. The aim of the present study was to determine whether or not IL-17-producing Th cells are present and whether IL-17 and other Th17-associated cytokines are involved in the immunological response to endotoxin in human airways.Segmental exposure to endotoxin and contralateral exposure to vehicle were performed in the lungs of healthy volunteers, with subsequent bronchoalveolar lavage 12 or 24 h after exposure to study local changes in cytokines and inflammatory cells.Endotoxin exposure increased concentrations of IL-17, IL-22 and their downstream effector molecules, human b-defensin-2 and IL-8/CXC chemokine ligand 8, in bronchoalveolar lavage fluid. Th cells with the capacity to produce IL-17 were found among the bronchoalveolar lavage cells, and expression of IL-17 mRNA correlated with expression of the transcription factor, retinoic-acidreceptor-related orphan receptor C variant 2. Moreover, endotoxin increased the numbers of neutrophils, macrophages and IL-17-producing T-cells, as well as the concentration of the Th17-regulating cytokines, IL-21 and IL-23.In conclusion, IL-17-producing Th cells are present, and IL-17, as well as other Th17-associated cytokines, is involved in the immunological response to endotoxin in human airways.

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Section: Increase In Effector Molecules Downstream Of Il-17 and Il-22supporting

confidence: 61%

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

Glader¹,

Smith²,

Malmhäll³

et al. 2010

Eur Respir J

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“…Furthermore, this processing in cDCs does not require caspase-1 or caspase-8, but depends on IL-21-mediated death (34). IL-21 can induce the expression of PR domain containing 1, with ZNF domain in multiple B lymphoma cell lines, and IL-21 induces STAT3 binding also bound interferon regulatory factor 4 (IRF4) in vivo (35,36), and Irf4 -/-mice showed impaired IL-21 induced Tfh cells differentiation (37). These results reveal broad cooperative gene regulation by STAT3 and IRF4.…”

Section: Signaling By Il-21mentioning

confidence: 99%

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Yuan

Wang

2016

Biomedical Reports

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Abstract. and its receptor (IL-21R) are broadly expressed on human B cells, activated T cells and other myeloid cells. IL-21 cooperates with IL-6 and transforming growth factor-β to regulate T-cell differentiation. IL-21-mediated human B cell and dendritic cells differentiation requires signal transducer and activator of transcription 3 (STAT3), and also induces B-cell apoptosis dependents on the Toll-like receptor signal. Recently, in vitro and in vivo experiments showed that IL-21/IL-21R regulate angiogenesis through STAT3. IL-21 signaling pathways are complex due to its cooperation with other transcriptional factors, such as interferon regulatory factor 4 and granulocyte-macrophage colony-stimulating factor. The Janus kinase-STAT pathway has been the most extensively studied. With the increase in the understanding of IL-21 biology in the context of each specific disease or pathological condition, IL-21 could be a new therapeutic target for immune-related disease.

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“…T H 17 differentiation requires retinoid-related orphan receptor (ROR)-γt, a transcription factor that is induced by TGF-β in combination with IL-6, -21, and -23, all of which activate STAT3 phosphorylation (4). Additionally, various host proteins such as aryl hydrocarbon receptor (AHR) (5-7), Runt-related transcription factor 1 (Runx1) (8), Interferon regulatory factor 4 (IRF4) (9), and Basic leucine zipper transcription factor ATF-like (BATF) (10) positively regulate T H 17 differentiation, whereas B-cell lymphoma 6 (Bcl-6) (11,12), Ets-1 (13), Nuclear receptor subfamily 2 group F member 6 (NR2F6) (14), Peroxisome proliferatoractivated receptor gamma (PPAR-γ) (15), Suppressor of cytokine signaling 3 (SOCS3) (16), and Liver X receptor (LXR) (17) inhibit generation of T H 17 cells. However, very few studies have addressed the regulation of T H 17 differentiation by microRNAs, a topic that should be investigated further.…”

mentioning

confidence: 99%

Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17–producing T-helper cell differentiation

Nakahama

Hanieh

Nguyen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

102

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Aryl hydrocarbon receptor (AHR) plays critical roles in various autoimmune diseases such as multiple sclerosis by controlling interleukin-17 (IL-17)-producing T-helper (T H 17) and regulatory T cells. Although various transcription factors and cytokines have been identified as key participants in T H 17 generation, the role of microRNAs in this process is poorly understood. In this study, we found that expression of the microRNA (miR)-132/212 cluster is upregulated by AHR activation under T H 17-inducing, but not regulatory T-inducing conditions. Deficiency of the miR-132/212 cluster prevented the enhancement of T H 17 differentiation by AHR activation. We also identified B-cell lymphoma 6, a negative regulator of T H 17 differentiation, as a potential target of the miR-212. Finally, we investigated the roles of the miR-132/212 cluster in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Mice deficient in the miR-132/212 cluster exhibited significantly higher resistance to the development of experimental autoimmune encephalomyelitis and lower frequencies of both T H 1 and T H 17 cells in draining lymph nodes. Our findings reveal a unique mechanism of AHR-dependent T H 17 differentiation that depends on the miR-132/212 cluster. dioxin receptor | autoimmunity | immune regulation

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IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype

Cited by 256 publications

References 34 publications

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17–producing T-helper cell differentiation

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