Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation

Mammalian interleukin-4 (IL-4) and IL-13 are T helper type 2 (Th2) cytokines with pleiotropic functions in immunity. They signal through receptors containing IL-4R alpha and IL-2R gamma or IL-13R alpha 1. In addition, a decoy receptor, IL-13R alpha 2, is known to exist and modulates the function of IL-13. The existence of fish orthologues to mammalian IL-4 and IL-13 is still under debate. However, the receptor chains have been predicted in zebrafish, and we have previously cloned IL-2R gamma and IL-13R alpha 2 in rainbow trout. In this study, we have cloned a further five novel trout IL-4/13 receptors. Thus, each of the IL-4R alpha, IL-13R alpha 1 and IL-13R alpha 2 chains has two copies. The identities of the receptors is supported by homology analysis, characteristic domain structure, phylogenetic tree analysis and synteny analysis in zebrafish. However, the characteristic WSXWS motif of structural importance in mammalian type I cytokine receptors is missing in all fish IL-4R alpha and IL-13R alpha 1 molecules. All the receptors have a characteristic domain structure that is similar to their mammalian counterparts except for IL-13R alpha 1b that has the N-terminal Ig domain missing. Since this Ig domain is a specific and critical binding unit for IL-13 but not for IL-4 signalling, its absence potentially converts the IL-13R alpha 1b into a receptor that can only signal via IL-4 ligation. The existence of duplicated receptor genes perhaps suggests that more ligands still remain to be discovered that will bind these receptors. The duplicated receptors are differentially expressed in most tissues and cell lines examined, and their expression can be modulated by LPS, polyIC and IFN-gamma in cell lines. In contrast, the T-cell stimulant phytohaemagglutinin increased the expression of IL-4R alpha 1 and IL-4R alpha 2, but not IL-13R alpha 1/2, suggesting a role of an IL-4-like molecule in T-cell growth/activation in fish.