Soluble Interleukin (IL)-15Rα Is Generated by Alternative Splicing or Proteolytic Cleavage and Forms Functional Complexes with IL-15

Elena Bulanova,Vadim Budagian,Erwin Duitman,Zane Orinska,Hans Krause,Rene Rückert,Norbert Reiling,Silvia Bulfone-Paus

doi:10.1074/jbc.m610036200

Abstract

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.

Highlights

N liferation of the CTLL cell line and interferon ␥ production by murine NK cells, which suggests a role in IL-15 transpresenta
Present in mouse serum [8] and the high affinity of IL-15R␣ we tested whether IL-151⁄7IL-15R␣ heterocomplexes toward IL-15, we questioned whether this soluble receptor exist in primary cells from normal and IL-15 receptor ␣ (IL-15R␣)Ϫ/Ϫ animals or molecule associates with IL-15 in biological fluids and cell cells and cell lines of various origin
Soluble Sushi Domain of IL-15R␣ and IL-15 Form Agonistic In this study, we show for the first time that an alternative

Summary

Introduction

N liferation of the CTLL cell line and interferon ␥ production by murine NK cells, which suggests a role in IL-15 transpresenta-. We demonstrated that spontaneous and inducible shedding of a natural soluble IL-15R␣ (sIL-15R␣) depends on activity of tumor necrosis factor-␣-converting enzyme (TACE/ ADAM17) and could be blocked by inhibitors of this metalloproteinase [8]. Notwithstanding, secreted forms of diverse membrane-linked proteins may appear as a result of an alternative splicing mechanism that gives rise to a polypeptide lacking transmembrane and/or other regions [9]. In some species, both modes can be operative, as shown for sIL-4R and sIL-6R (9 –11). Production of sion in both immune and nonimmune cell types and tissues [2]. growth hormone receptor by proteolytic cleavage in humans

Methods

Results

Conclusion