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+.
Lynn
W S
WS
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston.
Mathews
D
D
Cloyd
M
M
Wallwork
J C
JC
Thompson
A
A
Sachs
C
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002412:Cations; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D050356:Lipid Metabolism; D051379:Mice
D002412:Cations; D006888:Hydroxycholesterols; D000001:Calcimycin; C007997:25-hydroxycholesterol; D003907:Dexamethasone; D002118:Calcium