First in-depth analysis of the novel Th2-type cytokines in salmonid fish reveals distinct patterns of expression and modulation but overlapping bioactivities

• Published in: Oncotarget
• Main Authors: Wang, T., Johansson, P., Abos Gracia, Beatriz, Holt, A., Tafalla Piñeiro, Carolina, Jiang, Y., Wang, A., Xu, Q., Qi, Z., Huang, W., Costa, M. M., Díaz Rosales, Patricia, Holland, J. W., Secombes, C. J.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Impact Journals 2016
• Subjects: IL-4/13A and 13B; Immune response; Immunity; Immunology and Microbiology Section; Bioactivity; Expression; Rainbow trout Oncorhynchus mykiss; Type-2 immunity; Atlantic salmon
• Online Access: https://hdl.handle.net/20.500.12792/4758; http://hdl.handle.net/10261/290267; https://doi.org/10.18632/oncotarget.7295

IL-4 and IL-13 are closely related canonical type-2 cytokines in mammals and have overlapping bioactivities via shared receptors. They are frequently activated together as part of the same immune response and are the signature cytokines produced by T-helper (Th)2 cells and type-2 innate lymphoid cells (ILC2), mediating immunity against extracellular pathogens. Little is known about the origin of type-2 responses, and whether they were an essential component of the early adaptive immune system that gave a fitness advantage by limiting collateral damage caused by metazoan parasites. Two evolutionary related type-2 cytokines, IL-4/13A and IL-4/13B, have been identified recently in several teleost fish that likely arose by duplication of an ancestral IL-4/13 gene as a consequence of a whole genome duplication event that occurred at the base of this lineage. However, studies of their comparative expression levels are largely missing and bioactivity analysis has been limited to IL-4/13A in zebrafish. Through interrogation of the recently released salmonid genomes, species in which an additional whole genome duplication event has occurred, four genomic IL-4/13 loci have been identified leading to the cloning of three active genes, IL-4/13A, IL-4/13B1 and IL-4/13B2, in both rainbow trout and Atlantic salmon. Comparative expression analysis by real-time PCR in rainbow trout revealed that the IL-4/13A expression is broad and high constitutively but less responsive to pathogen-associated molecular patterns (PAMPs) and pathogen challenge. In contrast, the expression of IL-4/13B1 and IL-4/13B2 is low constitutively but is highly induced by viral haemorrhagic septicaemia virus (VHSH) infection and during proliferative kidney disease (PKD) in vivo, and by formalin-killed bacteria, PAMPs, the T cell mitogen PHA, and the T-cell cytokines IL-2 and IL-21 in vitro. Moreover, bioactive recombinant cytokines of both IL-4/13A and B were produced and found to have shared but also distinct bioactivities. Both cytokines rapidly induce ...