title: Identification of a cytotoxic form of dimeric interleukin-2 in murine tissues.
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.
authors.affiliation: Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine Wright State University, Dayton, Ohio, United States of America.
authors.forename: Lucile E
authors.initials: LE
authors.lastname: Wrenshall
authors.affiliation: Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine Wright State University, Dayton, Ohio, United States of America.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Clabaugh
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Cool
authors.affiliation: Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine Wright State University, Dayton, Ohio, United States of America.
authors.forename: Prakash
authors.initials: P
authors.lastname: Arumugam
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Grunwald
authors.affiliation: Eppley Institute for Cancer Research, University of Nebraska at Omaha, Omaha, Nebraska, United States of America.
authors.forename: Deandra R
authors.initials: DR
authors.lastname: Smith
authors.affiliation: Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine Wright State University, Dayton, Ohio, United States of America.
authors.forename: Gino C
authors.initials: GC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine Wright State University, Dayton, Ohio, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Miller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D019281:Dimerization; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D007376:Interleukin-2 / Q000737:chemistry* / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D007376:Interleukin-2