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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

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

Shim Juyoung K JK Caron Molly A MA Weatherly Lisa M LM Gerchman Logan B LB Sangroula Suraj S Hattab Siham S Baez Alan Y AY Briana Talya J TJ Gosse Julie A JA

Journal of applied toxicology : JAT 20190819 12

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 Ca<sup>2+</sup> influx into antigen-stimulated mast cells and subsequent degranulation. To determine the mechanism linking the TCS cytosolic Ca<sup>2+</sup> depression ...[more]

PMID: 31429102

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Project description:Background: As the number of allergic disease increases, studies to identify new treatments take on new urgency. Epigallocatechin gallate (EGCG), a major component of green tea, has been shown to possess a wide range of pharmacological properties, including anti-inflammation and anti-viral infection. In previous study, gallic acid (GA), a part of EGCG, has shown anti-allergic inflammatory effect. To improve on preliminary evidence that GA has allergy mitigating effect, we designed SG-SP1 based on GA, and aimed to assess the effects of SG-SP1 on mast cell-mediated allergic inflammation using various animal and in vitro models. Methods: For in vitro experiments, various types of IgE-stimulated mast cells (RBL-2H3: mast cell-like basophilic leukemia cells, and primary cultured peritoneal and bone marrow-derived mast cells) were used to determine the role of SG-SP1 (0.1-1 nM). Immunoglobulin (Ig) E-induced passive cutaneous anaphylaxis and ovalbumin-induced systemic anaphylaxis, standard animal models for immediate-type hypersensitivity were also used. Results: For in vitro, SG-SP1 reduced degranulation of mast cells by down-regulating intracellular calcium levels in a concentration-dependent manner. SG-SP1 decreased expression and secretion of inflammatory cytokines in activated mast cells. This suppressive effect was associated with inhibition of the phosphorylation of Lyn, Syk and Akt, and the nuclear translocation of nuclear factor-κB. Due to the strong inhibitory effect of SG-SP1 on Lyn, the known upstream signaling to FcεRI-dependent pathway, we confirmed the direct binding of SG-SP1 to FcεRI, a high affinity IgE receptor by surface plasmon resonance experiment. Oral administration of SG-SP1 hindered allergic symptoms of both anaphylaxis models evidenced by reduction of hypothermia, serum IgE, ear thickness, and tissue pigmentation. This inhibition was mediated by the reductions in serum histamine and interleukin-4. Conclusions: We determined that SG-SP1 directly interacts with FcεRI and propose SG-SP1 as a therapeutic candidate for mast cell-mediated allergic inflammatory disorders via inhibition of FcεRI signaling.

Project description:Triclosan antimicrobial molecular fluctuating energies of nonbonding electron pairs for the oxygen atom by ether bond rotations are reviewed with conformational computational chemistry analyses. Subsequent understanding of triclosan alternating ether bond rotations is able to help explain several material properties in Polymer Science. Unique bond rotation entanglements between triclosan and the polymer chains increase both the mechanical properties of polymer toughness and strength that are enhanced even better through secondary bonding relationships. Further, polymer blend compatibilization is considered due to similar molecular relationships and polarities. With compatibilization of triclosan in polymers a more uniform stability for nonpolar triclosan in the polymer solid state is retained by the antimicrobial for extremely low release with minimum solubility into aqueous solution. As a result, triclosan is projected for long extended lifetimes as an antimicrobial polymer additive. Further, triclosan rapid alternating ether bond rotations disrupt secondary bonding between chain monomers in the resin state to reduce viscosity and enhance polymer blending. Thus, triclosan is considered for a polymer additive with multiple properties to be an antimicrobial with additional benefits as a nonpolar toughening agent and a hydrophobic wetting agent. The triclosan material relationships with alternating ether bond rotations are described through a complete different form of medium by comparisons with known antimicrobial properties that upset bacterial cell membranes through rapid fluctuating mechanomolecular energies. Also, triclosan bond entanglements with secondary bonding can produce structural defects in weak bacterial lipid membranes requiring pliability that can then interfere with cell division. Regarding applications with polymers, triclosan can be incorporated by mixing into a resin system before cure, melt mixed with thermoplastic polymers that set on cooling into a solid or alternatively applied as a coating through several different methods with dissolving into an organic solvent and dried on by evaporation as a common means.

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

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

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