Effects of interleukins 2 and 12 on the levels of granzyme B and perforin and their mRNAs in tributyltin-exposed human natural killer cells

Abstract

Natural killer (NK) cells are a subset of lymphocytes that are capable of killing tumor cells, virally infected cells and antibody coated cells. Tributyltin (TBT) is a toxic chemical used for various industrial purposes such as: slime control in paper mills, disinfection of circulating industrial cooling waters, anti-fouling agents, and the preservation of wood. TBT can be found in edible items such as fish. A previous study showed that a 1 h exposure of NK cells to TBT caused persistent inhibition of NK-cell ability to destroy tumor cells in the 24 and 48 h periods following exposure and that this loss of function could be significantly prevented and/or reversed if the NK-stimulatory interleukins (IL) 2 or 12 were present during the 24 and 48 h periods. We had also shown that TBT exposure was able to significantly decrease the protein and mRNA levels of the cytotoxic proteins, granzyme B and perforin, and the phosphorylation of cAMP-response-element-binding protein (CREB) under these conditions. In this study we address the effects of IL-2 and IL-12 on the TBT-induced decreases in NK-cell levels of the cytotoxic proteins, their mRNAs, and CREB phosphorylation. IL-2 appeared to prevent/reverse TBT-induced declines in perforin protein levels and the mRNA for perforin seen in the 24 h period following a 1 h exposure to 300 nM TBT. However, the TBT-induced decreases in the levels of perforin and perforin mRNA seen in the 48 h period following a 1 h exposure to TBT were not statistically significantly prevented/reversed by IL-2. Additionally, the TBT-induced decreases in granzyme B, granzyme B mRNA, and CREB phosphorylation were not statistically significantly reversed by either IL-2 or IL-12 after 24 or 48 h.

Effect of tributyltin (TBT) in the metabolic activity of TBT‐resistant and sensitive estuarine bacteria

“…Therefore, the chronic negative effects of TBT, even in low concentrations, are worrisome. Indeed, a wide variety of organisms are affected by this compound (Fent, 1996; Bekri and Pelletier, 2004; Sousa et al, 2005; Thomas et al, 2005).…”

Activation of p44/42 MAPK plays a role in the TBT-induced loss of human natural killer (NK) cell function

“…Thus, the decreases in granzyme B and perforin expression seen with exposures to TBT (Thomas et al, 2004; and Thomas et al, 2005) cannot be explained by TBT-induced activation of p44/42, in contrast to the TBT-induced effects on lytic function. This indicates that other TBT-induced changes, such as p38 activation (Aluoch and Whalen, 2005; Aluoch et al,2006) or increases in cytosolic calcium ion (Lane et al, 2009), may be responsible for the decreases seen in these proteins.…”

“…Previous studies indicated that exposure to TBT decreases the lytic function of NK cells (Dudimah et al, 2007; Whalen et al, 1999), decreases their expression of cytolytic proteins (granzyme B and perforin) (Thomas, et al, 2004; Thomas et al, 2005), and activates mitogen activated protein kinases (MAPK), including p44/42 (Aluoch and Whalen, 2005; Aluoch et al, 2006; Aluoch et al, 2007). TBT-induced loss of NK function could leave exposed individuals with an increased risk of viral infection and /or tumor formation.…”

Highly Diastereoselective Synthesis of Substituted Pyrrolidines Using a Sequence of Azomethine Ylide Cycloaddition and Nucleophilic Cyclization

“…From all the results of the key reaction cascade detailed above, we demonstrated that we could tune the reaction path by selecting the right metal: stannylated derivative 11a followed path II, whereas silylated derivative 11b followed path I. Most importantly, to avoid the use of organotin due to its toxicity, we successfully forced the desired reaction (path II) even with silylated substrate 11b by adding n -Bu 4 NCl to rapidly cleave the C−Si bond as soon as the formamide was activated (entry 5). Adduct 12 was obtained as the major diastereomer in an excellent yield.…”