Abstract
Interleukin-2 (IL-2) is a multi-faceted cytokine, known for promoting proliferation, survival, and cell death depending on the cell type and state. For example, IL-2 facilitates cell death only in activated T cells when antigen and IL-2 are abundant. The availability of IL-2 clearly impacts this process. Our laboratory recently demonstrated that IL-2 is retained in blood vessels by heparan sulfate, and that biologically active IL-2 is released from vessel tissue by heparanase. We now demonstrate that heparanase digestion also releases a dimeric form of IL-2 that is highly cytotoxic to cells expressing the IL-2 receptor. These cells include “traditional” IL-2 receptor-bearing cells such as lymphocytes, as well as those less well known for IL-2 receptor expression, such as epithelial and smooth muscle cells. The morphologic changes and rapid cell death induced by dimeric IL-2 imply that cell death is mediated by disruption of membrane permeability and subsequent necrosis. These findings suggest that IL-2 has a direct and unexpectedly broad influence on cellular homeostatic mechanisms in both immune and non-immune systems.
Highlights
Interleukin-2 (IL-2) is a fascinating cytokine, with widely varying functions including promotion of apoptosis, proliferation and survival of lymphocytes [1]
Our laboratory recently reported that IL-2 is retained in the blood vessel wall by heparan sulfate [8,9] we showed that heparanase digestion of murine aortic tissue resulted in the release of biologically active, monomeric (15 kD) IL-2 [8]
Dimeric form of IL-2 is present in blood vessels Recent work from our laboratory demonstrated that IL-2 is present in blood vessels and is retained there by association with heparan sulfate (HS) [8,9]
Summary
Interleukin-2 (IL-2) is a fascinating cytokine, with widely varying functions including promotion of apoptosis, proliferation and survival of lymphocytes [1] Not surprisingly, these varied responses depend on the type of lymphocyte, and on the activation state of the cell. For example, occurs in activated T cells that are exposed to IL-2 and re-activated [2] This activationinduced cell death (recently renamed restimulation-induced cell death) is thought to be a feedback mechanism designed to limit the expansion and facilitate the down-regulation of antigen-specific immune responses [3]. While IL-2 is typically considered a monomeric protein, studies by Eitan, et al described a dimeric form of IL-2 that was cytotoxic to oligodendrocytes [5] This dimeric IL-2, extracted from fish optic neurons, was thought to be the result of the cross-linking of two IL-2 monomers by optic nerve-derived transglutaminase. Dimeric IL-2 was shown to induce apoptosis of oligodendrocytes after several hours, likely through a p53-related mechanism [7]
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