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Natural, Proteolytic Release of a Soluble Form of Human IL-15 Receptor a-Chain That Behaves as a Specific, High Affinity IL-15 Antagonist
- Source :
- Journal of Immunology, Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2004, 173, pp.1681-1688
- Publication Year :
- 2004
- Publisher :
- HAL CCSD, 2004.
-
Abstract
- IL-15 and IL-2 are two structurally and functionally related cytokines whose high affinity receptors share the IL-2R beta-chain and gamma-chain in association with IL-15R alpha-chain (IL-15R alpha) or IL-2R alpha-chain, respectively. Whereas IL-2 action seems restricted to the adaptative T cells, IL-15 appears to be crucial for the function of the innate immune responses, and the pleiotropic expression of IL-15 and IL-15R alpha hints at a much broader role for the IL-15 system in multiple cell types and tissues. In this report, using a highly sensitive radioimmunoassay, we show the existence of a soluble form of human IL-15R alpha (sIL-15R alpha) that arises from proteolytic shedding of the membrane-anchored receptor. This soluble receptor is spontaneously released from IL-15R alpha-expressing human cell lines as well as from IL-15R alpha transfected COS-7 cells. This release is strongly induced by PMA and ionomycin, and to a lesser extent by IL-1 beta and TNF-alpha. The size of sIL-15R alpha (42 kDa), together with the analysis of deletion mutants in the ectodomain of IL-15R alpha, indicates the existence of cleavage sites that are proximal to the plasma membrane. Whereas shedding induced by PMA was abrogated by the synthetic matrix metalloproteinases inhibitor GM6001, the spontaneous shedding was not, indicating the occurrence of at least two distinct proteolytic mechanisms. The sIL-15R alpha displayed high affinity for IL-15 and behaved as a potent and specific inhibitor of IL-15 binding to the membrane receptor, and of IL-15-induced cell proliferation (IC(50) in the range from 3 to 20 pM). These results suggest that IL-15R alpha shedding may play important immunoregulatory functions.
- Subjects :
- DNA, Complementary
[SDV.IMM] Life Sciences [q-bio]/Immunology
Glycosylphosphatidylinositols
[SDV]Life Sciences [q-bio]
Immunology
Biology
Lymphoma, T-Cell
Transfection
chemistry.chemical_compound
Cell surface receptor
Cell Line, Tumor
Chlorocebus aethiops
Animals
Humans
Immunology and Allergy
Protease Inhibitors
Receptor
Interleukin-15
COS cells
U937 cell
Receptors, Interleukin-15
Tumor Necrosis Factor-alpha
Ionomycin
Receptors, Interleukin-2
Dipeptides
U937 Cells
Molecular biology
Molecular Weight
[SDV] Life Sciences [q-bio]
Protein Subunits
Interleukin-15 receptor
Solubility
chemistry
Ectodomain
Interleukin 15
Culture Media, Conditioned
COS Cells
Tetradecanoylphorbol Acetate
[SDV.IMM]Life Sciences [q-bio]/Immunology
Glioblastoma
Cell Division
Interleukin-1
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 00221767 and 15506606
- Database :
- OpenAIRE
- Journal :
- Journal of Immunology, Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2004, 173, pp.1681-1688
- Accession number :
- edsair.doi.dedup.....787b43d9aba5e00027a7049fad60a285