The effect of environmental contaminants on mitogen-activated-protein kinase kinase kinase and Ras-GTPase activity in human natural killer cells
Toxic effects of environmental contaminants on the human immune system are not well understood; therefore, further studies to elucidate their consequence are necessary. Butyltins (BTs) contaminate the environment and are found in human blood. The BTs tributyltin (TBT) and dibutyltin (DBT) diminish the cytotoxic function and levels of key proteins of human natural killer (NK) cells. The brominated flame retardant (BFR) Tetrabromobisphenol A (TBBPA) has also been shown to have immunosuppressive effects on human NK cells. NK cells are an initial immune defense against tumors, virally-infected cells and antibody-coated cells and thus critical to human health. The signaling pathways that regulate NK cell functions include mitogen-activated protein kinases (MAPKs). Studies have shown that exposure to BTs and TBBPA lead to the activation of specific MAPKs and MAPK kinases (MAP2Ks) in human NK cells. MAP2K kinases (MAP3Ks) are upstream activators of MAP2Ks, which in turn activate MAPKs. The current study examined if BTs- and/or TBBPA-induced activation of MAP3Ks was responsible for MAP2K and thus, MAPK activation. This study examines the effects of TBT, DBT and TBBPA on the total levels of two MAP3Ks, c-Raf and ASK1, as well as activating and inhibitory phosphorylation sites on these MAP3Ks. In addition the immediate upstream activator of c-Raf, Ras, was examined for BT-induced alterations. Our results show significant activation of the MAP3K, c-Raf, in human NK cells within 10 minutes of TBT exposure and the MAP3K, ASK1, after 1 hour exposure to TBT. Furthermore, our results suggest that both TBT and DBT are impacting the regulation of c-Raf.
Lindsay J Celada,
"The effect of environmental contaminants on mitogen-activated-protein kinase kinase kinase and Ras-GTPase activity in human natural killer cells"
ETD Collection for Tennessee State University.