Time Course of the Effects of Tributyltin Exposures on eIF4B, eIF4E, and S6 in Human Immune Cells.

Abstract

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 InformationThis work was supported in part by grant 5U54CA163066 from the National Institutes of Health/National Cancer Institute.