Abstract
Taurine is an abundant free amino acid that interacts with the potent oxidant hypochlorous acid to form the less toxic and more stable oxidant taurine monochloramine (TauNHCl). TauNHCl has diverse cellular effects ranging from inhibiting the production of proinflammatory mediators to inhibiting cell proliferation and inducing cell death. We hypothesized that TauNHCl could activate a cell death pathway involving Bcl-2 members and the activation of caspase proteases. FL5.12 cells are lymphocytic cells that undergo apoptosis following interleukin-3 (IL-3) withdrawal. Therefore, cell death following TauNHCl treatment of FL5.12 cells was compared and contrasted with IL-3 withdrawal. We found that TauNHCl treatment activates a cell death pathway with kinetics very similar to IL-3 withdrawal. TauNHCl-treated cells undergo an annexin V-positive/propidium iodide-negative phase of death consistent with apoptosis. TauNHCl treatment results in a conformational change in BAX that is associated with its activation. Both Bcl-2 and, to a lesser degree, the dominant negative form of caspase-9 inhibit cell death following TauNHCl treatment. In contrast with IL-3 withdrawal, TauNHCl treatment of FL5.12 cells results in a rapid cell cycle arrest that is cell cycle phase-independent. These results demonstrate that TauNHCl treatment induces a rapid, cell cycle-independent proliferative arrest followed by the activation of a cell death pathway involving Bcl-2 family members and caspase activation.
Highlights
On activation, leukocytes generate large quantities of the strongly oxidizing species hypochlorous acid (HOCl).1 HOCl can directly oxidize a variety of biomolecules, it is believed that the predominant reaction is the formation of chloramines with the amine groups of protein or free amino acids
In contrast with IL-3 withdrawal, TauNHCl treatment of FL5.12 cells results in a rapid cell cycle arrest that is cell cycle phase-independent. These results demonstrate that TauNHCl treatment induces a rapid, cell cycle-independent proliferative arrest followed by the activation of a cell death pathway involving Bcl-2 family members and caspase activation
The family can be divided into those that inhibit (Bcl-2, Bcl-x, etc.) and those that promote cell death. Those that promote apoptosis can be further characterized as multidomain members (Bax, Bak, and Bok) with more extensive homology to Bcl-2 and BCL-2 homology domain 3 (BH3)-only family members, in which homology to Bcl-2 is limited to this single BH3 domain [10]
Summary
Leukocytes generate large quantities of the strongly oxidizing species hypochlorous acid (HOCl). HOCl can directly oxidize a variety of biomolecules, it is believed that the predominant reaction is the formation of chloramines with the amine groups of protein or free amino acids. HOCl can directly oxidize a variety of biomolecules, it is believed that the predominant reaction is the formation of chloramines with the amine groups of protein or free amino acids Of these reactions, the predominant formation is HOCl with taurine, a sulfur-containing -amino acid found in high concentrations in granulocytes and lymphocytes [1]. The role of Bcl-2 family members in TauNHCl-induced cell death has not been examined. Antiapoptotic members prevent the release of mitochondrial proteins such as cytochrome c, Smac/Diablo, and apoptosis-inducing factor (AIF), which are involved in caspase activation and DNA degradation, two biochemical hallmarks of apoptosis [11]. Current evidence supports a model in which Bcl-2 prevents the formation or opening of a large mitochondrial channel that contains the proapoptotic family member Bax or Bak [13]. The activated form of BAX can be detected using conformation-specific anti-
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