title: Identification of a gene for an ancient cytokine, interleukin 15-like, in mammals; interleukins 2 and 15 co-evolved with this third family member, all sharing binding motifs for IL-15Rα.
abstract: Interleukins 2 and 15 (IL-2 and IL-15) are highly differentiated but related cytokines with overlapping, yet also distinct functions, and established benefits for medical drug use. The present study identified a gene for an ancient third IL-2/15 family member in reptiles and mammals, interleukin 15-like (IL-15L), which hitherto was only reported in fish. IL-15L genes with intact open reading frames (ORFs) and evidence of transcription, and a recent past of purifying selection, were found for cattle, horse, sheep, pig and rabbit. In human and mouse the IL-15L ORF is incapacitated. Although deduced IL-15L proteins share only ~21 % overall amino acid identity with IL-15, they share many of the IL-15 residues important for binding to receptor chain IL-15Rα, and recombinant bovine IL-15L was shown to interact with IL-15Rα indeed. Comparison of sequence motifs indicates that capacity for binding IL-15Rα is an ancestral characteristic of the IL-2/15/15L family, in accordance with a recent study which showed that in fish both IL-2 and IL-15 can bind IL-15Rα. Evidence reveals that the species lineage leading to mammals started out with three similar cytokines IL-2, IL-15 and IL-15L, and that later in evolution (1) IL-2 and IL-2Rα receptor chain acquired a new and specific binding mode and (2) IL-15L was lost in several but not all groups of mammals. The present study forms an important step forward in understanding this potent family of cytokines, and may help to improve future strategies for their application in veterinarian and human medicine.
authors.affiliation: Institute for Comprehensive Medical Science, Fujita Health University, Dengakugakubo 1-98, Toyoake, Aichi, 470-1192, Japan, dijkstra@fujita-hu.ac.jp.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Dijkstra
authors.forename: Fumio
authors.initials: F
authors.lastname: Takizawa
authors.forename: Uwe
authors.initials: U
authors.lastname: Fischer
authors.forename: Maik
authors.initials: M
authors.lastname: Friedrich
authors.forename: Veronica
authors.initials: V
authors.lastname: Soto-Lampe
authors.forename: Christophe
authors.initials: C
authors.lastname: Lefèvre
authors.forename: Matthias
authors.initials: M
authors.lastname: Lenk
authors.forename: Axel
authors.initials: A
authors.lastname: Karger
authors.forename: Taei
authors.initials: T
authors.lastname: Matsui
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002417:Cattle; D019143:Evolution, Molecular; D006736:Horses; D006801:Humans; D019409:Interleukin-15 / Q000145:classification / Q000235:genetics* / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010802:Phylogeny; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000145:classification / Q000235:genetics / Q000276:immunology; D011817:Rabbits; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012756:Sheep; D013552:Swine
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D020033:Protein Isoforms