Butyltins (BTs), tributyltin (TBT) and dibutyltin (DBT) are organotin compounds that have been used in a variety of industrial applications; as a result, these compounds have been found in human blood. Interleukin (IL)-6 is a proinflammatory mediator that is produced by T lymphocytes and monocytes. It is responsible for immune response regulation as well as tissue repair and cellular growth. Both BTs decrease the ability of human natural killer cells to destroy tumor cells and alter the secretion of proinflammatory cytokines tumor necrosis factor alpha, interferon gamma and IL-1 beta (β) from human lymphocytes ex vivo. Here, we show that BTs alter the secretion of IL-6 from increasingly reconstituted preparations of human immune cells. IL-6 secretion was examined after 24 hour, 48 hour or 6 day exposures to TBT and DBT in highly enriched human natural killer cells, monocyte-depleted peripheral blood mononuclear cells (PBMCs), PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes (PBMCs + granulocytes). The results indicated that both BTs altered IL-6 secretion from all cell preparations. Significant decreases of IL-6 secretion were seen at the highest concentration of TBT (200 nm) and DBT (5-2.5 μm) while the lower concentrations of DBT (0.05 and 0.1 μm) caused elevation of IL-6 secretion. The data indicate that BT-induced alterations of IL-6 secretion from immune cells may be a significant consequence of BT exposures that may potentially affect immune competence.
Tributyltin (TBT) is an organotin compound that contaminates the environment and has been found in human blood samples. TBT‐exposed mammals have shown increased incidences of tumors. Previously, we have shown that TBT was able to interfere with the ability of human natural killer (NK) lymphocytes to lyse tumor target cells. Our recent studies have shown that TBT is able to alter the secretion of the pro‐inflammatory cytokine tumor necrosis factor alpha (TNFα) from immune cells. The results indicate that concentrations of TBT of 200 – 2.5 nM caused significant alterations of TNFα secretion. Interleukin 6 (IL‐6) is produced by T lymphocytes and monocytes and is important in regulating our immune response to infections and tissue damage. Due to the important role that IL‐6 plays in immune responsiveness, it is important to understand whether exposures to TBT are able to disrupt its secretion. Peripheral blood mononuclear cells (PBMCs) were exposed to TBT at concentrations of 0–200nM and monitored for secretion of IL‐6 at 24h, 48 h, and 6 days using enzyme‐linked immunosorbent assay (ELISA). TBT at concentrations of 10–200 nM for 24 h, 48 h, or 6 days decreased the levels of IL‐6 secreted by PBMCs. Supported by NIH grants 2T34GM007663–3 and 5U54CA163066–02.
Constitutive activation of the nuclear factor kappa B (NF-κB) is common in melanoma, promoting tumor growth and metastasis. Therefore, targeting the NF-κB pathway is a possible therapeutic option. However, NF- κB activity is critical for the development and function of immune cells. Melanoma bearing C57BL/6 mice received BMS-345541, a selective inhibitor of the inhibitor of κB kinase (IKKβ). No difference was observed in tumor size. Tumors were analyzed by flow cytometry and intracellular cytokine staining revealed an early induction of Interleukin-4 (IL-4) within the leukocyte compartment of the tumor, with drug treatment. The production of IL-4 leads to an early switch to a tumor promoting T helper 2 (Th2) driven immune response, counteracting the anti-tumor effect of IKKβ inhibition. IL-4 receptor (IL-4R) expression on human melanoma cells has been documented; however the effects of IL-4 on these cells have generated contradictory reports. In vitro IL-4 delivery did not alter either the proliferative capacity of IL-4R expressing melanoma cell lines or their sensitivity to BMS-345541. In nude mice bearing an IL-4 transduced human A375 melanoma , BMS345541 was given in combination with IL-4R blocking antibody. This combination inhibited tumor growth compared to BMS-345541 treatment alone, similar to previous studies in C57BL/6 mice. IL-4R antagonists are in clinical trials for the treatment of asthma, making the translational prospects of this study extraordinarily viable.
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