Evolution of Th2 responses: characterization of IL-4/13 in sea bass (Dicentrarchus labrax L.) and studies of expression and biological activity

Valentina Stocchi,Francesco Buonocore,Elisa Randelli,Alberto Pallavicini,Massimo Mazzini,Chris J Secombes,Marco Gerdol,Tiehui Wang,Giuseppe Scapigliati

doi:10.1038/s41598-017-02472-y

Valentina Stocchi, Francesco Buonocore + Show 7 more

Open Access

https://doi.org/10.1038/s41598-017-02472-y

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Abstract

Th2 immunity is a primary host defence against metazoan pathogens and two of the important cytokines involved in this immune response in mammals are IL-4 and IL-13. Recently the origin and evolution of Th2 immune responses have been investigated in fish where a molecule with relatedness to both IL-4 and IL-13 is present, termed IL-4/13. Different IL-4/13 paralogues (IL-4/13 A and IL-4/13B) exist in teleost fish. In this paper, we have focused on the IL-4/13 isoforms found in the European sea bass (Dicentrarchus labrax L.). Two tandem duplicated but divergent IL-4/13 A isoforms and one IL-4/13B are present, a unique situation compared to other teleosts. These genes were studied in terms of their in vitro and in vivo transcript levels after different treatments and their biological activities after production of the recombinant isoforms. The results show that the presence of these three paralogues is associated with different activities, both in terms of their expression profiles and the ability of the proteins to modulate the expression of immune genes in head kidney leukocytes. It is clear that the initiation and control of type-2 responses in seabass is complex due to the presence of multiple IL-4/13 isoforms with overlapping but distinct activities.

Highlights

Th2 immunity is a primary host defence against metazoan pathogens and two of the important cytokines involved in this immune response in mammals are IL-4 and IL-13
It has been proposed that the duplication of these IL-4/13 genes arose after the third round (3R) of whole genome duplication (WGD) that occurred in the teleost fish ancestor[21]
In the spotted gar (Lepisosteus oculatus), a 2R bony fish, a single IL-4/13 gene is present between KIF3A and RAD5017 and at least two IL-4/13 related genes have been identified in the elephant shark (Callorhinchus milii), a 2R cartilaginous fish[22]

Summary

Introduction

Th2 immunity is a primary host defence against metazoan pathogens and two of the important cytokines involved in this immune response in mammals are IL-4 and IL-13. The origin and evolution of Th2 immune responses have been investigated in fish where a molecule with relatedness to both IL-4 and IL-13 is present, termed IL-4/13. Two tandem duplicated but divergent IL-4/13 A isoforms and one IL4/13B are present, a unique situation compared to other teleosts These genes were studied in terms of their in vitro and in vivo transcript levels after different treatments and their biological activities after production of the recombinant isoforms. In a recent paper on allergic responses mediated by IL-4 and IL-13, it was evidenced that IL-4 mediates many specific functions, including fine-tuning of the Th2 response through its ability to initiate, perpetuate or shut off the allergic response through the activation of multiple signalling pathways (STAT6 and IRS-2), whilst IL-13 preferentially drives the development of the disease pathological features manifested by non-bone marrow– derived cells[10]. A possible Th2 inflammatory process has been discovered in coho salmon (Oncorhynchus kisutch) after a disease outbreak due to the salmon louse (Lepeophtheirus salmonis)[26] and recombinant IL-4/13 molecules have been produced in zebrafish[27], carp[28], rainbow trout[24], Japanese pufferfish[29] and goldfish[30] to investigate the fish Th2-like regulatory mechanisms

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