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Vertebrates Regulatory Mechanism in Ancient Zebrafish Essential Role of IL-4 and IL-4Rα Interaction in Adaptive Immunity of Zebrafish: Insight into the Origin of Th2-like Regulatory Mechanism in Ancient This information is current as Vertebrates of October 1, 2021. Lv-yun Zhu, Ping-ping Pan, Wei Fang, Jian-zhong Shao and Li-xin Xiang J Immunol 2012; 188:5571-5584; Prepublished online 30 April 2012; Downloaded from doi: 10.4049/jimmunol.1102259 http://www.jimmunol.org/content/188/11/5571 Supplementary http://www.jimmunol.org/content/suppl/2012/04/30/jimmunol.110225 http://www.jimmunol.org/ Material 9.DC1 References This article cites 69 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/188/11/5571.full#ref-list-1 Why The JI? Submit online. by guest on October 1, 2021 • Rapid Reviews! 30 days* from submission to initial decision • 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 Essential Role of IL-4 and IL-4Ra Interaction in Adaptive Immunity of Zebrafish: Insight into the Origin of Th2-like Regulatory Mechanism in Ancient Vertebrates Lv-yun Zhu, Ping-ping Pan, Wei Fang, Jian-zhong Shao, and Li-xin Xiang The roles of IL-4 and IL-4Ra in Th2-mediated immunity have been well characterized in humans and other mammals. In contrast, few reports have been documented in ancient vertebrates. Several putative IL-4– and IL-4Ra–like molecules were identified recently from a few fish species, providing preliminary insight into the occurrence of Th2-type immunity in teleosts. However, functional determination still is required to address this hypothesis. To this end, these two molecules were characterized functionally in zebrafish (Danio rerio). Besides the identification of a full-length IL-4Ra molecule and an isoform lacking most of the cytoplasmic region as predicted previously, two novel alternatively spliced soluble variants with the extracellular domain only also were identified. Zebrafish IL-4Ra (DrIL-4Ra) shared overall conserved structural features of the IL-4Ra family. Immuno- Downloaded from fluorescence staining showed that DrIL-4Ra distributed on B cells. In vitro binding assays demonstrated that zebrafish IL-4 (DrIL-4) can bind specifically to DrIL-4Ra. In vivo administration of DrIL-4 significantly upregulated B cell proliferation and Ab production. These DrIL-4–elicited immune responses were downregulated by the administration of zebrafish soluble IL-4Ra or by DrIL-4Ra blockade using anti–DrIL-4Ra Abs. In addition, Th2-related cytokines or transcription factors were upregulated by DrIL-4. The DrIL-4–DrIL-4Ra interaction promoted CD40 expression on B cells and enhanced the CD154–CD40 costimulatory response, both of which are crucial for the initiation of Th2-type immunity. To our knowledge, this is the first report showing that http://www.jimmunol.org/ a possible Th2-mediated regulatory mechanism may have appeared before the divergence of teleosts and mammals. These results add greater insight into the evolutionary history of adaptive immunity. The Journal of Immunology, 2012, 188: 5571–5584. n mammals, naive CD4+ T lymphocytes can differentiate into the two Th subsets in humans is associated with the development various Th subsets, such as Th1, Th2, Th3, Th17, and Th25, of autoimmune and allergic diseases (2, 10, 13, 17–19). I with distinct cytokine profiles and functions, in which Th1 IL-4 is an important member of the class I cytokine family with and Th2 are the two well-characterized subsets (1–6). The Th1 four a helix structures that is secreted predominantly by activated subset secretes IFN-g, TNF-a, and IL-2, which are important for Th2 cells (16, 20). It induces Th2-mediated immune responses by by guest on October 1, 2021 Th1-mediated cellular immunity (7, 8). The Th2 subset produces upregulating the expression of MHC class II, CD23, and IL-4R on IL-4, IL-5, and IL-13, which promote further Th2 development of B cells (9, 14, 20, 21). It has an anti-inflammatory effect owing to its stimulated CD4+ Th cells and a variety of Th2-mediated humoral efficient inhibition of the production of proinflammatory cytokines, immune responses, including B cell proliferation and activation, such as TNF-a,IL-1a,IL-1b, IL-6, and IL-8. It also plays a crucial Ig production, and Ig class switching (1, 2, 8–16). Imbalance of role in mediating allergic responses. In this process, IL-4 stimulates the proliferation of mast cells with IL-13 and promotes Ig class switching to IgE that binds to high-affinity Fcε receptors on the College of Life Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, surfaces of mast cells, basophils, and eosinophils, leading to the de- Hangzhou 310058, People’s Republic of China; and Key Laboratory of Animal granulation and production of inflammatory mediators when it is Virology of Ministry of Agriculture, Hangzhou 310058, People’s Republic of China cross-linked by an Ag (10, 11, 14, 15, 18, 19). IL-4 exerts its bio- Received for publication August 4, 2011. Accepted for publication March 26, 2012. logical functions by interacting with IL-4R (18, 22). The latter is a This work was supported by grants from the Hi-Tech Research and Development heterodimer composed of a specific a-chain (IL-4Ra or IL-4BP) and Program of China (863) (2012AA092202), the National Basic Research Program of acommong-chain (g ). The g also is coutilized by IL-2, IL-7, IL-9, China (973) (2012CB114404, 2012CB114402), the National Natural Science Foun- c c dation of China (30871936, 31072234, 31172436) and the Program for Key Innova- IL-13, IL-15, and IL-21 for the activation of signaling pathways (23, tive Research Team of Zhejiang Province (2010R50026). 24). As a class I cytokine receptor, IL-4Ra has specific and high The sequences presented in this article have been submitted to GenBank (http://www. affinities (Kd = 20–300 pM) in the recognition and binding to IL-4 ncbi.nlm.nih.gov/genbank/) under accession numbers EF523375.1, EF523376.1, (14, 20, 24–26). It could be detected on a number of hematopoietic EF523377.1, and EF523378.1. or nonhematopoietic cell surfaces, including endothelial, epithelial, Address correspondence and reprint requests to Prof. Jian-zhong Shao and Assoc. Prof. Li-xin Xiang, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou 310058, muscle, fibroblast, hepatocyte, and brain cells (14, 27). Zhejiang, People’s Republic of China. E-mail addresses: [email protected] (J.-z.S.) The molecular and functional characterization of IL-4, IL-4Rs, and [email protected] (L.-x.X.) and downstream signaling pathways in Th2-mediated immunity The online version of this article contains supplemental material. has been well documented in humans and other mammals (28–32). Abbreviations used in this article: BS3, bis(sulfosuccinimidyl) suberate; gc, common In contrast, there are few reports regarding their occurrence and g-chain; DC, dendritic cell; DrIL-4, zebrafish IL-4; DrIL-4Ra, zebrafish IL-4Ra; DrIL-4Ra-iso, zebrafish IL-4Ra isoform; EST, expressed sequence tag; FN III, fi- functions in adaptive immunity in ancient vertebrates (33–37). In bronectin type III; KLH, keyhole limpet hemocyanin; ORF, open reading frame; a previous study, we identified an IL-4–like gene from pufferfish sCD154, soluble CD154; sDrIL-4Ra, zebrafish soluble IL-4Ra;sDrIL-4Ra-iso, (Tetraodon nigroviridis) (11), and two similar IL-4–like genes, IL- zebrafish soluble IL-4Ra isoform; UTR, untranslated region. 4/13A and IL-4/13B, were cloned subsequently from zebrafish Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 (Danio rerio) (12). It shows that zebrafish IL-4/13A has a perfect www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102259 5572 ROLE OF IL-4–IL-4Ra INTERACTION IN Th2-LIKE IMMUNITY IN FISH TATA box and GATA3 binding motif in the proximal promoter free DNase I (Qiagen). Zebrafish IL-4Ra (DrIL-4Ra) and soluble IL-4Ra regions of the gene. However, IL-4/13B lacks such a box and motif (sDrIL-4Ra) cDNAs were cloned using the primers shown in Table I. The in its proximal promoter regions. This result suggests that IL-4/13B 39 and 59 full RACE core sets were used following the manufacturer’s instructions (Takara). Seminested or nested PCR was adopted in RACE. lacks the complete transcription elements. In addition, a search of PCR products were purified using a gel extraction kit (Qiagen), ligated into the expressed sequence tags (ESTs) in the National Center for a pUCm-T vector (Takara), and transformed into Escherichia coli Top10 Biotechnology Information database revealed several ESTs for competent cells (Invitrogen). Plasmid DNA was extracted by the plasmid zebrafish IL-4/13A, whereas none was found for zebrafish IL-4/ Miniprep method and then sequenced on a MegaBACE 1000 sequencer (GE Healthcare) using a DYEnamic ET dye terminator cycle sequencing 13B. As a consequence, IL-4/13A might be the real zebrafish kit (Pharmacia). Full-length cDNAs were assembled by catabolite gene IL-4, but more functional evidence still is needed.
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