title: Tributyltin exposure causes decreased granzyme B and perforin levels in 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 in shower curtains and the preservation of wood. TBT can be found in edible items such as dairy products and fish. This study investigates the mechanism by which TBT exposure decreases the immune function of human NK cells, in vitro. Cytotoxic function, the expression of the cytotoxic proteins (granzyme B and perforin), and cAMP response element binding protein (CREB) phosphorylation were examined. NK cells exposed to 300 nM TBT for 1 h showed no significant decrease in cytotoxic function, levels of granzyme B and perforin, or phosphorylation of CREB. However, mRNA levels for the cytotoxic proteins were significantly decreased. A 24 h exposure to 200 nM TBT caused significant decreases in cytotoxic function, levels of granzyme B and perforin, and levels of granzyme B and perforin mRNA. When NK cells were exposed to 300 nM TBT for 1h followed by a 24 h period in TBT-free media, again there were significant decreases in NK cell cytotoxic function, levels of granzyme B and perforin and their mRNA. A 1h exposure to 300 nM TBT followed by a 48 h period in TBT-free media showed similar changes in cytotoxic function and levels of granzyme B and perforin as seen after 24 h in TBT-free media. Additionally, both of these exposures showed significant decreases in phosphorylation of CREB. These results indicate that TBT exposures can disrupt the transcription of granzyme B and perforin and that this disruption cannot be entirely accounted for by a decrease in phosphorylated CREB (phosphoCREB) levels.
authors.affiliation: Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
authors.forename: LeeShawn D
authors.initials: LD
authors.lastname: Thomas
authors.forename: Hemangini
authors.initials: H
authors.lastname: Shah
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Green
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Bankhurst
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Whalen
mesh_terms: D000328:Adult; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D053804:Granzymes; D006801:Humans; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D054353:Perforin; D010766:Phosphorylation; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000378:metabolism*; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D014220:Trialkyltin Compounds; D054353:Perforin; C011559:tributyltin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases