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Cytokines the Production of Proinflammatory Regulates Th17 Differentiation by Limiting the E3 Ubiquitin Ligase Adaptor Ndfip1

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Cytokines the Production of Proinflammatory Regulates Th17 Differentiation by Limiting the E3 Ubiquitin Ligase Adaptor Ndfip1 The E3 Ubiquitin Ligase Adaptor Ndfip1 Regulates Th17 Differentiation by Limiting the Production of Proinflammatory Cytokines This information is current as of September 29, 2021. Hilda E. Ramon, Allison M. Beal, Yuhong Liu, George Scott Worthen and Paula M. Oliver J Immunol 2012; 188:4023-4031; Prepublished online 7 March 2012; doi: 10.4049/jimmunol.1102779 Downloaded from http://www.jimmunol.org/content/188/8/4023 Supplementary http://www.jimmunol.org/content/suppl/2012/03/07/jimmunol.110277 http://www.jimmunol.org/ Material 9.DC1 References This article cites 42 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/188/8/4023.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 29, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The E3 Ubiquitin Ligase Adaptor Ndfip1 Regulates Th17 Differentiation by Limiting the Production of Proinflammatory Cytokines Hilda E. Ramon,*,1 Allison M. Beal,†,1 Yuhong Liu,‡ George Scott Worthen,‡ and Paula M. Oliver*,† Ndfip1 is an adaptor for the E3 ubiquitin ligase Itch. Both Ndfip1- and Itch-deficient T cells are biased toward Th2 cytokine pro- duction. In this study, we demonstrate that lungs from Ndfip12/2 mice showed increased numbers of neutrophils and Th17 cells. This was not because Ndfip12/2 T cells are biased toward Th17 differentiation. In fact, fewer Ndfip12/2 T cells differentiated into Th17 cells in vitro due to high IL-4 production. Rather, Th17 differentiation was increased in Ndfip12/2 mice due to increased numbers of IL-6–producing eosinophils. IL-6 levels in mice that lacked both Ndfip1 and IL-4 were similar to wild-type controls, Downloaded from and these mice had fewer Th17 cells in their lungs. These results indicate that Th2 inflammation, such as that observed in Ndfip12/2 mice, can increase Th17 differentiation by recruiting IL-6–producing eosinophils into secondary lymphoid organs and tissues. This may explain why Th17 cells develop within an ongoing Th2 inflammatory response. The Journal of Immunology, 2012, 188: 4023–4031. D4 T cells can differentiate into different Th subsets Th1 and Th2 cells can directly inhibit Th17 differentiation, Th17 http://www.jimmunol.org/ according to cues from their immediate cytokine envi- cells commonly occur alongside Th1 and Th2 cells in inflamma- C ronment. Th17 cells are a distinct group of CD4 Th cells tory settings such as in inflammatory bowel disease and asthma. that have been shown to protect against specific bacterial and fungal Atopic asthma is characterized by Th2-mediated inflammation in pathogens by producing proinflammatory cytokines that mediate the lung and is often accompanied by eosinophilia, high serum IgE neutrophil recruitment (1). Although they can play protective levels, and airway hyperreactivity (11). Although this disease is roles, Th17 cells can also worsen the pathogenesis of inflamma- defined by the hallmark Th2-mediated inflammation, high levels tory diseases such as multiple sclerosis, arthritis, inflammatory of IL-17, as well as Th17 cells, are present in the lungs of asth- bowel disease, and asthma (2, 3). matic patients (12–14). Furthermore, high levels of IL-17 and Th17 differentiation can be either promoted or prevented by neutrophil accumulation are normally seen in more severe cases of by guest on September 29, 2021 various cytokines. For example, CD4 Th cells can differentiate into asthma (15, 16), including steroid-resistant asthma (17, 18). Th17 Th17 cells in response to TGF-b and the proinflammatory cytokine cells have been shown to contribute to lung inflammation in IL-6 (4, 5). Although TGF-b and IL-6 are sufficient for their mouse models of asthma through the recruitment of neutrophils differentiation, IL-23 signaling promotes long-term maintenance (19–22) that can promote tissue damage and by inducing lung of the Th17 cell lineage, allowing Th17 cells to fully differentiate stromal cell and epithelial cells to produce proinflammatory cyto- and proliferate (6). Additionally, IL-1 together with IL-6 can fa- kines and chemokines (23–26). cilitate Th17 differentiation by increasing expression of retinoic- Nedd4 family interacting protein 1 (Ndfip1) is an adaptor related orphan receptor gt and IFN response factor-4 and inducing protein that binds to and augments the function of the E3 ligase higher levels of IL-17 production (7). In contrast, Th17 differen- Itch (27). Itch has been shown to ubiquitylate and cause the tiation is inhibited by IL-2 as well as the Th2 and Th1-specific degradation of JunB (28), a transcription factor that promotes the cytokines IL-4 and IFN-g (8–10). Although cytokines made by expression of IL-2, IL-4, and IL-5 (29). In the absence of Ndfip1, activated CD4 T cells accumulate high levels of JunB and become Th2 polarized (27). We recently reported that Ndfip12/2 mice *School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; †Depart- naturally develop Th2-mediated inflammation in the skin, gas- ment of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, trointestinal tract, and lungs and die prematurely (27, 30). These Philadelphia, PA 19104; and ‡Department of Pediatrics, Children’s Hospital of Phil- adelphia, Philadelphia, PA 19104 mice have increased percentages of activated CD4 T cells in their 1 spleens and lymph nodes that are Th2 biased, as well as eosin- H.E.R. and A.M.B. contributed equally to this work. ophilia. Additionally, they have high circulating levels of IgE and Received for publication September 26, 2011. Accepted for publication February 2, 2012. IL-5 in the serum. Histological analysis revealed infiltrating in- This work was supported in part by National Institutes of Health Grants T-32-AI- flammatory cells in the perivascular regions in the lung and goblet 055428-06, R-03-AR-057144, and R-01-AI-093566. cell hyperplasia (27). Importantly, neutrophils were also evident Address correspondence and reprint requests to Prof. Paula M. Oliver, Children’s in the perivascular regions of the lung, as well as within the al- Hospital of Philadelphia, 3615 Civic Center Boulevard, 816F Abramson Research veolar space. Given the reported role of Th17 cells in lung in- Center, Philadelphia, PA 19104. E-mail address: [email protected] flammation and in the recruitment of neutrophils into the airways, The online version of this article contains supplemental material. we sought to determine whether Ndifp12/2 regulates Th17 dif- Abbreviations used in this article: BAL, bronchoalveolar lavage; DKO, double- ferentiation. knockout; Ndfip1, Nedd4 family interacting protein 1; WT, wild-type. In this report, we show that mice lacking Ndfip1 have increased Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 numbers of Th17 cells. This finding suggested a scenario in which www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102779 4024 Ndfip1 REGULATES Th17 DIFFERENTIATION Ndfip1 acts to prevent Th17 differentiation, much like it does for cultured in 48-well plates using 5 3 105 cells/well and activated with Th2 differentiation. On the contrary, in vitro, Ndfip12/2 T cells plate-bound anti-CD3 (5 mg/ml) and anti-CD28 (5 mg/ml; BD Pharmin- were defective in becoming Th17 cells. This is because increased gen). Th17-differentiating conditions included TGF-b (5 ng/ml; Pepro- 2/2 Tech) and IL-6 (20 ng/ml; R&D Systems) or TGF-b (0.5 ng/ml), IL-6 (20 IL-4 production by Ndfip1 T cells inhibit Th17 differentia- ng/ml), IL-1 (20 ng/ml; PeproTech), and IL-23 (50 ng/ml) (R&D Systems). tion. Thus, Ndfip1 promotes Th17 differentiation by inhibiting Cells were cultured for 5 d and analyzed for IL-17 and IL-4 production by production of IL-4. In addition, our data show that although flow cytometry by intracellular cytokine staining. Supernatants were col- IL-4 directly inhibits Th17 differentiation in vitro, the Th2 in- lected at 20–24 h to measure IL-2 production by ELISA. In some of the 2/2 experiments, IL-4 (BioLegend) and IL-2 (BD Biosciences) blocking Abs flammatory environment in Ndfip1 mice promotes the differ- were added at the initiation of the cultures (20 mg/ml). entiation of Th17 in vivo by increasing the numbers of IL-6– producing eosinophils. Together, these data suggest that Th2 Measurement of cytokines by ELISA responses can promote Th17 responses in vivo. This might help to ELISA was performed to measure cytokines from either serum or spleen explain why Th17 cells develop in the setting of inflammatory cultures. For serum, mice were bled, and serum was collected using diseases such as asthma. minicollect tubes from Greiner bio-one and stored at 280˚C until used for ELISA. Spleen cultures were set up using 4 3 106 splenocytes/well in a round-bottom 96-well plate. Soluble anti-CD3 (5 mg/ml) was used Materials and Methods to activate T cells. Supernatants were collected at 24 h after stimulation Mice andplacedat280˚C until used. For IL-6 production from spleen cul- tures, splenocytes were stimulated with PMA (1 mM) and ionomycin 2/2 Ndfip1 mice have been previously described (27).
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