Modulation of NF-κB activation by HOCl

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During phagocytosis of bacteria, neutrophils produce hypochlorous acid (HOCl) into phagolysosomes or into the extracellular medium.  HOCl is formed from H₂O₂ and Cl^- ion by myeloperoxidase [10].  HOCl is a strong oxidant that kills phagocytosed bacteria, but can also react with amines to produce chloramines and N-chlorinated derivatives which have long lifetimes [60].  These chloramines retain the oxidizing capacities of HOCl and are also playing a protecting effect on the surrounding cells.  Among these chloramines, taurine chloramine (TauCl) is generated in great amount in HOCl-producing neutrophils because these cells contain high concentration of taurine, a free amino acid not incorporated in proteins.  Despite a pioneer work suggested that HOCl can activate NF-κB in lymphocytic cells [61], following studies revealed that HOCl-derived chloramines are potent NF-κB inhibitors.  For example, TauCl was shown to decrease LPS-induced NF-κB activation and IKK activity in alveolar macrophages, which results in inhibition of iNOS and TNFα gene expression [62].  The molecular mechanism of this inhibition relied on oxidation of IκBα methionine 45, which renders it resistant to TNF-induced degradation [63].  Other works demonstrated that ammonia monochloramine (NH₂Cl) and glycine chloramine (GlyCl), two others neutrophils-derived oxidants, but not TauCl, was capable of inhibiting TNF-induced NF-κB activation via the same molecular mechanism [64].  This apparent discrepancy is explainable by the fact the TauCl is membrane-impermeable, whereas NH₂Cl and GlyCl are membrane permeable, and are thus capable of regulating redox signalling pathways more efficiency and at much lower concentrations than TauCl [65, 66].  The results obtained by Kanayama et al., describing an inhibitory effect of TauCl on NF-κB activation, are explainable by the fact that they added TauCl to cells in culture medium that contains other amino acids, whereas others authors used amino acid-free solutions.  Since chloramines can undergo transchlorination reactions with other amines in the medium, they likely transformed in more permeable chloramines like GlyCl [67].  Altogether, these results demonstrate that, on the contrary of H₂O₂, HOCl and its derivatives are apparently strong inhibitor of the NF-κB pathway, which can result in a diminution of the inflammatory response in HOCl-producing cells.