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Although IL-21 has also been discovered in birds, amphibians, and fish, to date, no functional studies have been reported for any nonmammalian IL-21 molecule. We have sequenced an IL-21 gene (tIL-21) in rainbow trout, which has a six-exon\/five-intron structure, is expressed in immune tissues, and is induced by bacterial and viral infection and the T cell stimulant PHA. In contrast to mammals, calcium ionophore and PMA act synergistically to induce tIL-21. Recombinant tIL-21 (rtIL-21) induced a rapid and long-lasting (4\u201372 h) induction of expression of IFN-\u03b3, IL-10, and IL-22, signature cytokines for Th1-, Th2-, and Th17-type responses, respectively, in head kidney leukocytes. However, rtIL-21 had little effects on the expression of other cytokines studied. rtIL-21 maintained the expression of CD8\u03b1, CD8\u03b2, and IgM at a late stage of stimulation when their expression was significantly decreased in controls and increased the expression of the Th cell markers CD4, T-bet, and GATA3. Intraperitoneal injection of rtIL-21 confirmed the in vitro bioactivity and increased the expression of IFN-\u03b3, IL-10, IL-21, IL-22, CD8, and IgM. Inhibition experiments revealed that the activation of JAK\/STAT3, Akt1\/2, and PI3K pathways were responsible for rtIL-21 action. This study helps to clarify the role of IL-21 in lower vertebrates for the first time, to our knowledge, and suggests IL-21 is a likely key regulator of T and B cell function in fish.<\/jats:p>","DOI":"10.4049\/jimmunol.1001203","type":"journal-article","created":{"date-parts":[[2010,12,16]],"date-time":"2010-12-16T05:31:21Z","timestamp":1292477481000},"page":"708-721","source":"Crossref","is-referenced-by-count":157,"title":["Functional Characterization of a Nonmammalian IL-21: Rainbow Trout <i>Oncorhynchus mykiss<\/i> IL-21 Upregulates the Expression of the Th Cell Signature Cytokines IFN-\u03b3, IL-10, and IL-22"],"prefix":"10.1093","volume":"186","author":[{"given":"Tiehui","family":"Wang","sequence":"first","affiliation":[{"name":"Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen , Aberdeen AB24 2TZ ,","place":["United Kingdom"]}]},{"given":"Patricia","family":"Diaz-Rosales","sequence":"additional","affiliation":[{"name":"Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen , Aberdeen AB24 2TZ ,","place":["United Kingdom"]}]},{"given":"Maria M","family":"Costa","sequence":"additional","affiliation":[{"name":"Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen , Aberdeen AB24 2TZ ,","place":["United Kingdom"]},{"name":"Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Cient\u00edficas , Vigo ,","place":["Spain"]}]},{"given":"Scott","family":"Campbell","sequence":"additional","affiliation":[{"name":"Marine Scotland Science, Marine Laboratory , Aberdeen AB11 9DB ,","place":["United Kingdom"]}]},{"given":"Michael","family":"Snow","sequence":"additional","affiliation":[{"name":"Marine Scotland Science, Marine Laboratory , Aberdeen AB11 9DB ,","place":["United Kingdom"]}]},{"given":"Bertrand","family":"Collet","sequence":"additional","affiliation":[{"name":"Marine Scotland Science, Marine Laboratory , Aberdeen AB11 9DB ,","place":["United Kingdom"]}]},{"given":"Samuel A M","family":"Martin","sequence":"additional","affiliation":[{"name":"Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen , Aberdeen AB24 2TZ ,","place":["United Kingdom"]}]},{"given":"Christopher J","family":"Secombes","sequence":"additional","affiliation":[{"name":"Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen , Aberdeen AB24 2TZ ,","place":["United Kingdom"]}]}],"member":"286","published-online":{"date-parts":[[2011,1,15]]},"reference":[{"key":"2025032410590755900_r1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/35040504","article-title":"Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function","volume":"408","author":"Parrish-Novak","year":"2000","journal-title":"Nature"},{"key":"2025032410590755900_r2","doi-asserted-by":"crossref","first-page":"11439","DOI":"10.1073\/pnas.200360997","article-title":"Cloning of a type I cytokine receptor most related to the IL-2 receptor \u03b2 chain","volume":"97","author":"Ozaki","year":"2000","journal-title":"Proc. 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