Soluble Interleukin IL-15Ralpha is generated by alternative splicing or proteolytic cleavage and forms functional complexes with IL-15.
Interleukin 15 (IL-15) is a pleiotropic cytokine that is hardly detectable in biological fluids. Here, we show that IL-15 forms functional heterocomplexes with soluble high affinity IL-15 receptor alpha (IL-15Ralpha) chain in mouse serum and cell-conditioned medium, which prevents IL-15 detection by ELISA. We also demonstrate that two soluble IL-15Ralpha (sIL-15Ralpha) sushi domain isoforms are generated through a novel alternative splicing mechanism within the IL-15Ralpha gene. These isoforms potentiate IL-15 action by promoting the IL-15-mediated proliferation of the CTLL cell line and interferon gamma production by murine NK cells, which suggests a role in IL-15 transpresentation. Conversely, a full-length sIL-15Ralpha ectodomain released by tumor necrosis factor-alpha-converting enzyme (TACE)-dependent proteolysis inhibits IL-15 activity. Thus, a dual mechanism of sIL-15Ralpha generation exists in mice, giving rise to polypeptides with distinct properties, which regulate IL-15 function.
Bulanova
Elena
E
Department of Immunology and Cell Biology and Immunochemistry and Biochemical Microbiology, Research Center Borstel, Borstel D-23845, Germany. ebulanova@fz-borstel.de
Budagian
Vadim
V
Duitman
Erwin
E
Orinska
Zane
Z
Krause
Hans
H
Rückert
Rene
R
Reiling
Norbert
N
Bulfone-Paus
Silvia
S
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency; D053647:Receptors, Interleukin-15 / Q000096:biosynthesis / Q000172:deficiency
C508025:Il15ra protein, mouse; D019409:Interleukin-15; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D053647:Receptors, Interleukin-15; D007371:Interferon-gamma; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse