Intracellular Ca2+ and cytotoxicity

Following injury or activation in some immune cell lines, elevation of intracellular Ca2+ concentration (Cai2+) is an early and major event that precedes cell death. Agents shown to elevate Cai2+ and to result subsequently in the death of some cells include human immunodeficiency virus (HIV) (in T4+ cells), 25-hydroxy cholesterol, tumor necrosis factor (TNF), cyclosporine, dexamethasone, alpha-interferon, and Ca2+ ionophores. The effects of these agents, both on Cai2+ and on cytotoxicity, are additive. This type of Ca2+-related cytotoxicity may be associated with either accelerated synthesis of triglycerides (TNF), accelerated synthesis of cholesterol ester (25-hydroxy cholesterol), or cholesterol (HIV) and terminally with declining synthesis of structural phospholipid. Agents that can lower Cai2+ (e.g., phorbol esters, diglycerides, lipoproteins [LDL], oleic acid, or serum) under appropriate conditions ameliorate the Ca2+-induced cytotoxicity. Metabolism of other divalent metals, i.e., Zn2+ and Cd2+, also become altered with cell injury, e.g., glucocorticoids elevate Cai2+, but block uptake of Zn2+. These observations support the idea that chronic elevation of Cai2+ by many chemically unrelated agents leads to cell death by creating imbalance both in cell biosynthetic mechanisms--especially in those controlling lipid metabolism--as well as creating imbalances in metabolism of other trace metals, especially Zn2+.