Tributyltin (TBT) is an organotin that has been used as a biocide in a variety of industrial applications such as wood preservation, antifouling paint, and antifungal agents. It contaminates the marine environment, has been found in human blood samples, and appears to increase tumor incidence in mammals. Interleukin 1 beta (IL-1�) is a pro-inflammatory cytokine that promotes cell growth, tissue repair, and immune response regulation. IL-1� appears to increase the invasiveness of certain tumors. Monocyte-depleted peripheral blood mononuclear cells (MD-PBMCs) are a preparation that primarily consists of T and NK lymphocytes. This cell preparation exhibits increased secretion of IL-1� when exposed to TBT at concentrations that have been found in human blood (5-25 nM). The aim of the current study is to examine the signaling pathway(s) that may be involved in the TBT-induced increases in IL-1� secretion from MD-PBMCs. MD-PBMCs were treated with inhibitors of pathways that regulate IL-1� secretion (IL-1� cleavage inhibitor, ERK � pathway inhibitors (PD98059, U0126), p38 inhibitor (SB202190), and NF?B inhibitor (BAY 11-7085)) 1h prior to adding TBT concentrations of 5, 10, and 2.5 nM for 24h.  Levels of IL-1� were monitored using an enzyme-linked immunosorbent assay (ELISA). Results indicated that caspase-1was not involved in TBT-induced increases in IL-1� secretion. NF?B inhibition prevented any IL-� secretion, even from control cells. However, inhibition of both ERK � and p38 diminished the ability of TBT to stimulate IL-1� secretion from MD-PBMCs. It appears that both the ERK � and p38 signaling pathways may be needed for TBT to increase secretion of IL-1� from immune cells.  This suggests that TBT may be stimulating pathways that regulate secretion of inflammatory cytokines (including IL-1�). Such a stimulation has the potential to fuel cancer cell proliferation and invasiveness. Supported by NIH grant 5U54CA163066-02.

Mechanism of tributyltin-stimulated interleukin-1 beta secretion from human lymphocytes

248th National Meeting (2014)

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