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-Chain That Behaves as a Specific, High Affinity IL-15 Antagonist1
Groupe de Recherche Cytokines et Récepteurs en Immunologie et Cancérologie, Département de Cancérologie, Institut National de la Santé et de la Recherche Médicale Unité 601, Institut de Biologie, Nantes, France
IL-15 and IL-2 are two structurally and functionally related cytokines whose high affinity receptors share the IL-2R 
-chain and 
-chain in association with IL-15R 
-chain (IL-15R) or IL-2R -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 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 (sIL-15R) that arises from proteolytic shedding of the membrane-anchored receptor. This soluble receptor is spontaneously released from IL-15R-expressing human cell lines as well as from IL-15R transfected COS-7 cells. This release is strongly induced by PMA and ionomycin, and to a lesser extent by IL-1 and TNF-. The size of sIL-15R (42 kDa), together with the analysis of deletion mutants in the ectodomain of IL-15R, 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 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 (IC50 in the range from 3 to 20 pM). These results suggest that IL-15R shedding may play important immunoregulatory functions.
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