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Measuring Proliferation of Vascular Smooth Muscle Cells Using Click Chemistry

The ability of a cell to proliferate is integral to the normal function of most cells, and dysregulation of proliferation is at the heart of many disease ...

Wright State University

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. 

Identification of a cytotoxic form of dimeric interleukin-2 in murine tissues.

Many nonlymphoid cell types express at least two, if not all three, subunits of the IL-2R; although, compared with lymphocytes, relatively little is known about how IL-2 affects the function of nonlymphoid cells. The limited information available suggests that IL-2 has a substantial impact on cells such as gastrointestinal epithelial cells, endothelial cells, and fibroblasts. In a previous report from our laboratory, we noted that IL-2 and IL-2Rβ-deficient mice lose smooth muscle cells over time, eventually resulting in aneurysmal aortas and ectatic esophagi. This finding, combined with our work showing that IL-2 surrounds vascular smooth muscle cells by association with perlecan, led us to ask whether vascular smooth muscle cells express an IL-2R. Toward this end, we reported the expression of IL-2Rβ on human and murine vascular smooth muscle cells. We now report that vascular smooth muscle cells express all three subunits of the IL-2R, and that expression of IL-2Rα varies with vascular smooth muscle cell phenotype. Furthermore, we show that, through a functional IL-2R, IL-2 initiates signaling pathways and impacts vascular smooth muscle cell function. Finally, we demonstrate that IL-2 expression increases upon initiation of conditions that promote intimal hyperplasia, suggesting a mechanism by which the IL-2/IL-2R system may impact this widespread vascular pathology.

Prakash Arumugam

Department of Neuroscience,
Cell Biology,
and Physiology,
Department of Neuroscience, Cell Biology, and Physiology

Wright State University

Measuring Proliferation of Vascular Smooth Muscle Cells Using Click Chemistry

Prakash Arumugam

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Neuroscience,Cell Biology,and Physiology,Department of Neuroscience, Cell Biology, and Physiology

Wright State University

Measuring Proliferation of Vascular Smooth Muscle Cells Using Click Chemistry

Department of Neuroscience,
Cell Biology,
and Physiology,
Department of Neuroscience, Cell Biology, and Physiology