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.
The underlying inflammation present in chronic airway diseases is orchestrated by increased secretion of CC and CXC chemokines that selectively recruit the leukocyte populations into the pulmonary system. Human chemokines, eotaxins (CCL11 and CCL26), RANTES, and interleukin (IL)-8, are dramatically upregulated through G-protein receptors in cell inflammation, including human asthma. In previous studies, a series of new glucocorticoid antedrugs (GCAs) were synthesized as derivatives of isoxazoline and oxime, and their pharmacological properties based on the antedrug concepts were evaluated. Utilizing both human airway epithelium (HAE) and eosinophil (EOS) cell culture models, we carried out studies to test the hypothesis that new GCA cell treatment would ameliorate Th-1/Th-2-driven secretion of these asthmatic biomarkers, eotaxins (CCL11 and CCL26), RANTES, and IL-8 chemokines, that would in turn decrease recruitment, proliferation, and activation of EOS cells. Results demonstrate that isoxazoline and oxime derivatives exhibit concentration-dependent inhibition, and specifically the compound No. 7 decreases significantly the secretion of eotaxins, RANTES, and IL-8 in cytokine-stimulated HAE cells. It was shown that EOS proliferation and activation were reduced considerably, and cell apoptosis occurred when exposed to nonfluorinated isoxazoline derivatives. These results provide evidence that concentration and structural manipulation of GCAs could increase the anti-inflammatory potency in treatment of chronic diseases, including asthma.
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