title: Functional characterization of a nonmammalian IL-21: rainbow trout Oncorhynchus mykiss IL-21 upregulates the expression of the Th cell signature cytokines IFN-gamma, IL-10, and IL-22.
abstract: In mammals, IL-21 is a common γ chain cytokine produced by activated CD4(+) T cells and NKT cells that acts on multiple lineages of cells. 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 (4-72 h) induction of expression of IFN-γ, 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 CD8α, CD8β, 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-γ, 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.
authors.affiliation: Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB24 2TZ, United Kingdom.
authors.forename: Tiehui
authors.initials: T
authors.lastname: Wang
authors.forename: Patricia
authors.initials: P
authors.lastname: Diaz-Rosales
authors.forename: Maria M
authors.initials: MM
authors.lastname: Costa
authors.forename: Scott
authors.initials: S
authors.lastname: Campbell
authors.forename: Michael
authors.initials: M
authors.lastname: Snow
authors.forename: Bertrand
authors.initials: B
authors.lastname: Collet
authors.forename: Samuel A M
authors.initials: SA
authors.lastname: Martin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Secombes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008969:Molecular Sequence Data; D029141:Novirhabdovirus / Q000276:immunology; D017686:Oncorhynchus mykiss / Q000276:immunology*; D018353:Rhabdoviridae Infections / Q000276:immunology / Q000821:virology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D015009:Yersinia Infections / Q000276:immunology / Q000382:microbiology; D044124:Yersinia ruckeri / Q000276:immunology; D000097043:Interleukin-22; D000098546:Interleukin-21
chemical_list: D007371:Interferon-gamma; D016753:Interleukin-10; D007378:Interleukins; D000097043:Interleukin-22; D000098546:Interleukin-21