Abstract
Natural killer (NK) cells destroy (lyse) tumor cells, virally infected cells, and antibody-coated cells. Previous studies indicated that exposure to the environmental contaminant tributyltin (TBT) decreases the lytic function of NK cells and activates mitogen-activated protein kinases (MAPK), including p44/42 (Aluoch and Whalen Toxicology 209:263–277, 2005). If activation of p44/42 is required for TBT-induced decreases of lytic function, then activation of p44/42 to similar extents by pharmacological agents such as phorbol 12-myristate 13-acetate (PMA) should mimic to some extent changes induced in NK cells with TBT exposures. NK cells were exposed to PMA concentrations between 0.25 and 10 nM for 10 min, 1 h, and 6 h before determining the lytic function (51Cr release assay) and phosphorylation state of MAPKs (Western blot). A 1-h exposure of NK cells to 5 nM PMA resulted in a loss of lytic function of 47%. Western blot analysis showed that a 1-h exposure to 5 nM PMA caused a sixfold increase in phospho-p44/42 levels. Previous studies showed a fivefold increase in phospho-p44/42 in response to a 1-h exposure to 300 nM TBT. Exposure to 300 nM TBT caused about a 40% decrease in lytic function. This study supports the hypothesis that p44/42 activation (as seen with TBT exposures) can cause a loss of NK-cell lytic function.
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Abraha A, Whalen MM. The role of p44/42 activation in tributyltin-induced inhibition of human natural killer cells: effects of MEK inhibitors. J Appl Toxicol. 2009;29:165–73.
Aluoch AO, Whalen MM. Tributyltin-induced effects on MAP kinases p38 and p44/42 in human natural killer cells. Toxicology. 2005;209:263–77.
Aluoch AO, Odman-Ghazi SO, Whalen MM. Alteration of an essential NK cell signaling pathway by low doses of tributyltin in human natural killer cells. Toxicology. 2006;224:229–37.
Aluoch AO, Odman-Ghazi SO, Whalen MM. Pattern of MAP kinases p44/42 and JNK activation by non-lethal doses of tributyltin in human natural killer cells. Arch Toxicol. 2007;81:271–7.
Biron CA, Byron KS, Sullivan JL. Severe herpes virus in an adolescent without natural killer cells. New Engl J Med. 1989;320:1731–5.
Dudimah FD, Odman-Ghazi SO, Hatcher F, Whalen MM. Effect of tributyltin (TBT) on the ATP levels in human natural killer cells: relationship to TBT- induced decreases in NK function. J Appl Toxicol. 2007;27:86–94.
Fleisher G, Koven N, Kamiya H, Henle W. A non-X-linked syndrome with susceptibility to severe Epstein–Barr virus infections. J Pediatr. 1982;100:727–30.
Hanna N. Expression of metastatic potential of tumor cells in young nude mice is correlated with low levels of natural-killer cell mediated cytotoxicity. Int J Cancer. 1980;26:675–90.
Hanson RD, Grisolano JL, Lay TJ. Consensus AP-1 and CRE motifs upstream from the human cytotoxic serine protease B (CSP-B/CGL-1) gene synergizes to activate transcription. Blood. 1993;82:2749–57.
Kannan K, Tanabe S, Tatsukawa R. Occurrence of butyltin residues in certain foodstuffs. Bull Environ Contam Toxicol. 1995a;55:510–6.
Kannan K, Tanabe S, Tatsukawa R, Williams RJ. Butyltin residues in fish from Australia, Papua New Guinea and the Solomon Islands. Int J Environ Anal Chem. 1995b;61:263–73.
Kannan K, Tanabe S, Iwata H, Tatsukawa R. Butyltins in muscle and liver of fish collected from certain Asian and Oceanian countries. Environ Pollut. 1995c;90:279–90.
Kannan K, Senthilkumar K, Giesy JP. Occurrence of butyltin compounds in human blood. Environ Sci Technol. 1999;33:1776–9.
Kiessling R, Haller O. Natural killer cells in the mouse, an alternative surveillance mechanism? Contemp Top Immunobiol. 1978;8:171–201.
Kimbrough RD. Toxicity and health effects of selected organotins compounds: a review. Environ Health Perspect. 1976;14:51–6.
Lane R, Ghazi SO, Whalen MM. Increases in cytosolic calcium ion levels in human natural killer cells in response to butyltin exposure. Arch Environ Contam Toxicol. 2009;57(4):816–25.
Laughlin RB, Linden O. Fate and effects of organotin compounds. Ambio. 1985;14:88–94.
Loganathan BG, Kannan K, Owen DA, Sajwan KS. Butyltin compounds in freshwater ecosystems. In: Lipnick RL, Hermens J, Jones K, Muir D, editors. Persistent, bioaccumulative, and toxic chemicals. I Fate and Exposure, Am. Chem. Soc. London: Oxford University Press; 2000.
Lotzova E. Definition and function of natural killer cells. Natural Immun. 1993;12:177–93.
Middlebrook JL, Leatherman DL. Binding of T-2 toxin to eukaryotic cell ribosomes. Biochem Pharmacol. 1989;38:3103–10.
O’Shea J, Ortaldo JR. The biology of natural killer cells: insight into the molecular basis of function. In: Lewis CE, McGee JOD, editors. The natural killer cell. Oxford: IRL; 1992. p. 1–40.
Roper WL. Toxicological profile for tin. USA: U.S. Department of Health and Human Services. Agency for Toxic Substances and Disease Registry; 1992.
Shifrin VI, Anderson P. Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J Biol Chem. 1999;274:13985–92.
Tanabe S, Prudente M, Mizuno T, Hasegawa J, Iwata H, Miyazaki N. Butyltin contamination in marine mammals from north Pacific and Asian coastal waters. Environ Sci Technol. 1998;32:193–8.
Thomas LD, Shah H, Green SA, Bankhurst AD, Whalen MM. Tributyltin exposure causes decreased granzyme B and perforin levels in human natural killer cells. Toxicology. 2004;200:221–33.
Thomas LD, Shah H, Bankhurst AD, Whalen MM. Effects of interleukins 2 and 12 on the levels of granzyme B and perforin and their mRNAs in tributyltin-exposed human natural killer cells. Arch Toxicol. 2005;79:711–20.
Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376.
Vivier E, Nunes JA, Vely F. Natural killer cell signaling pathways. Science. 2004;306:1517–9.
Whalen MM. Inhibition of human natural killer cell function in vitro by glucose concentrations seen in poorly controlled diabetes. Cell Physiol Biochem. 1997;7:53–60.
Whalen MM, Loganathan BG, Kannan K. Immunotoxicity of environmentally relevant concentrations of butyltins on human natural killer cells in vitro. Environ Res. 1999;81:108–16.
Whalen MM, Williams TB, Green SA, Loganathan BG. Interleukins 2 and 12 produce recovery of cytotoxic function in tributyltin-exposed human natural killer cells. Environ Res. 2002;88:189–209.
Whalen MM, Loganathan BG, Yamashita N, Saito T. Immunomodulation of human natural killer cell cytotoxic function by triazine and carbamate pesticides. Chemico-Biological Int. 2003;145:311–9.
Yamada S, Fuji Y, Mikami E, Kawamura N, Hayakawa J. Small-scale survey of organotin compounds in household commodities. J AOAC Int. 1993;76:436–41.
Acknowledgment
This research was supported by Grant 2S06GM-08092-34 from the National Institutes of Health.
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Dudimah, F.D., Griffey, D., Wang, X. et al. Activation of p44/42 MAPK plays a role in the TBT-induced loss of human natural killer (NK) cell function. Cell Biol Toxicol 26, 435–444 (2010). https://doi.org/10.1007/s10565-010-9154-6
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DOI: https://doi.org/10.1007/s10565-010-9154-6