Antimicrobial agent triclosan suppresses mast cell signaling via phospholipase D inhibition.

ABSTRACT: Humans are exposed to the antimicrobial agent triclosan (TCS) through use of TCS-containing products. Exposed tissues contain mast cells, which are involved in numerous biological functions and diseases by secreting various chemical mediators through a process termed degranulation. We previously demonstrated that TCS inhibits both Ca²⁺ influx into antigen-stimulated mast cells and subsequent degranulation. To determine the mechanism linking the TCS cytosolic Ca²⁺ depression to inhibited degranulation, we investigated the effects of TCS on crucial signaling enzymes activated downstream of the Ca²⁺ rise: protein kinase C (PKC; activated by Ca²⁺ and reactive oxygen species [ROS]) and phospholipase D (PLD). We found that TCS strongly inhibits PLD activity within 15 minutes post-antigen, a key mechanism of TCS mast cell inhibition. In addition, experiments using fluorescent constructs and confocal microscopy indicate that TCS delays antigen-induced translocations of PKC?II, PKC? and PKC substrate myristoylated alanine-rich C-kinase. Surprisingly, TCS does not inhibit PKC activity or overall ability to translocate, and TCS actually increases PKC activity by 45 minutes post-antigen; these results are explained by the timing of both TCS inhibition of cytosolic Ca²⁺ (~15+ minutes post-antigen) and TCS stimulation of ROS (~45 minutes post-antigen). These findings demonstrate that it is incorrect to assume that all Ca²⁺ -dependent processes will be synchronously inhibited when cytosolic Ca²⁺ is inhibited by a toxicant or drug. The results offer molecular predictions of the effects of TCS on other mammalian cell types, which share these crucial signal transduction elements and provide biochemical information that may underlie recent epidemiological findings implicating TCS in human health problems.

SUBMITTER: Shim JK 

PROVIDER: S-EPMC6861621 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature