Tributyltin (TBT) is an environmental contaminant due to its use in a variety of applications. It has been used to prevent the growth of fouling organisms on the hulls of ships and due to this use, as well as others, it has entered the food chain. It is found in human blood (ranging as high as 261 nM). Inflammatory cytokines are important mediators of the response to injury or infection. However, if their levels are increased in the absence of a needed immune response, they can lead to chronic inflammation that is associated with a number of pathologies including, rheumatoid arthritis, Crohn’s disease, atherosclerosis, and cancer. TBT can increase the synthesis of pro‐inflammatory cytokines such as interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL‐1β), and interleukin 6 (IL‐6) in human immune cells. TBT appears to utilize the ERK1/2 and/or p38 MAPK pathways to stimulate pro‐inflammatory cytokine production by immune cells. MAPK pathways have the capacity to regulate translation including processes leading to the phosphorylation (activation) of eukaryotic initiation factor 4E (eIF4E), eIF4B, and the S6 ribosomal subunit. The current studies examine the levels and phosphorylation state of eIF4E, eIF4B and S6K after 10 min, 1 h, 6 h, and 24 h exposures to TBT in monocyte‐depleted peripheral blood mononuclear cells (MD‐PBMCs). Initial results indicate that TBT caused increased phosphorylation (activation) of eIF4B (S406) and S6 within 10 minutes of exposure. These results suggest that TBT is elevating the synthesis of key pro‐inflammatory cytokines in immune cells by its ability to activate translation. Support or Funding Information This work was supported in part by grant 5U54CA163066 from the National Institutes of Health/National Cancer Institute.
Dibutyltin (DBT) is an organotin that contaminates the environment due to its uses as a stabilizer in polyvinylchloride, PVC plastics and as a deworming agent in certain poultry products. DBT has been found in drinking water and other beverages due to leaching from PVC plastics used during the distribution of drinking water and storage of beverages such as beers and wines. DBT has been found in human blood at levels as high as 0.3μM. Inflammatory cytokines are key mediators in the response to injury or infection. However, if their levels are increased in the absence of a necessary immune response, chronic inflammation is possible. Chronic inflammation is associated with various disorders including, rheumatoid arthritis, Crohn’s disease, atherosclerosis, and cancer. DBT can increase the production of pro‐inflammatory cytokines such as interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL‐1β), and interleukin 6 (IL‐6) in human immune cells. DBT appears to utilize the ERK 1/2 and/or p38 MAPK pathways to stimulate pro‐inflammatory cytokine production in immune cells. MAPK pathways are capable of regulating translation including processes leading to the phosphorylation (activation) of eukaryotic initiation factor 4E (eIF4E), eIF4B, and the S6 ribosomal subunit. The current study examines the levels and phosphorylation state of eIF4E, eIF4B and S6 after 6‐hour and 24‐hour exposures to DBT in peripheral blood mononuclear cells (PBMCs). DBT (at all concentrations) caused a robust increase in phosphorylation (activation) of eIF4B (S406) within 6‐hour exposure across all donors. Additionally, elevated levels of phosphorylated and total S6 were observed at 0.1 μM in all donors in 6‐hour exposures. At 24 hours of exposure, increases in P‐S6, S6 and P‐eIF4B (S406) begin to taper off with increases observed sporadically amongst donors. These results suggest that DBT may be in part elevating the production of key pro‐inflammatory cytokines in immune cells by its ability to activate translation.
Tributyltin (TBT) is an organotin that widely contaminates the environment due to multiple uses, primarily as an anti‐fouling agent to prevent the growth of organisms on the hull of boats and ships. Due to these uses and a variety of others, TBT has entered the human food chain and has been found in human blood at concentrations as high as 261 nm. Inflammatory cytokines are imperative mediators in response to an injury or infection. If the levels of inflammatory cytokines are increased without a need, they can lead to chronic inflammation. Chronic inflammation has been associated with several pathologies such as rheumatoid arthritis, Crohn's disease, and cancer. Previous studies have shown that TBT can increase the synthesis of pro‐inflammatory cytokines interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL‐1β), and interleukin 6 (IL‐6) in human immune cells. TBT seems to utilize the ERK 1/2 and/or p38 MAPK pathways to stimulate pro‐inflammatory cytokine production by immune cells. MAPK pathways have the ability to regulate translation and more specifically processes that can lead to the phosphorylation/activation of eukaryotic initiation factor 4B (eIF4B). The current study examines the levels and phosphorylation state of eIF4B after 10‐minute exposures to TBT in peripheral blood mononuclear cells (PBMCs). Initial results indicate that TBT causes increased phosphorylation/ activation of P‐eIF4B (S406) at all concentrations and P‐eIF4B (S422) at the lowest concentration (2.5 nm). Results suggest that TBT may, at least in part, increase production of pro‐inflammatory cytokines in PBMCs due to its ability to activate translation.
Tributyltin (TBT) contaminates the environment due to its use as a biocide. It is found in human blood (ranging as high as 261 nM). TBT is able to increase the synthesis of pro‐inflammatory cytokines such as interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL‐1β), and interleukin 6 (IL‐6) in human immune cells. This TBT‐induced increase in pro‐inflammatory cytokines could contribute to chronic inflammation, which is a risk factor for a number of diseases including several cancers. TBT appears to utilize the ERK1/2 and/or p38 MAPK pathways to stimulate pro‐inflammatory cytokine synthesis in immune cells. MAPK pathways have the capacity to regulate translation including processes leading to the phosphorylation (activation) of eukaryotic initiation factor 4E (eIF4E), eIF4B, and the S6 ribosomal subunit. We hypothesize that TBT may influence the activation state of these translational regulators as part of its mechanism of increasing cytokine synthesis. Studies to examine the levels and phosphorylation state of eIF4E, eIF4B and S6K after varying lengths of exposure to TBT in monocyte‐depleted peripheral blood mononuclear cells (MD‐PBMCs) were carried out. Initial results suggest that TBT caused increased phosphorylation (activation) of eIF4E and S6. These results may indicate that TBT is elevating the synthesis of key pro‐inflammatory cytokines in immune cells by its ability to activate translation.Support or Funding InformationNIH Grant 5U54CA163066This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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