Tributyltin-induced alterations of essential signaling pathways in human natural killer cells
NK cells are lymphocytes in the non-adaptive immune system that protect the body against intracellular pathogens and eliminate tumor cells. Tributyltin (TBT) is a toxic chemical that has been detected in human foods as well as in human blood. The role of TBT in immunosuppression has been described, including inhibition of the human NK-cell cytotoxic function. These studies investigated the molecular mechanism by which TBT causes inhibition of cytotoxic function and how NK cells suppress apoptosis by TBT concentrations that inhibit cytotoxic function. Upon NK cell binding to lysis-sensitive tumor cells, an intracellular pathway is activated, which generally begins with activation of non-receptor protein tyrosine kinases (PTKs) and ends with mitogen-activated protein kinase (MAPK)-mediated release of lytic granules toward the contacted target cell. MAPKs, MAPK kinases (MAP2Ks), PKs, BAX and BCL -2, and p53 were examined. Continuous in vitro exposure to 300 nM TBT for 1 h decreased the NK cell cytotoxic function with concomitant increases in phosphorylated forms of both p38 and p44/42 but not the total levels of either of these enzymes. Similar results were obtained with 500 nM TBT treatment. A 1 h exposure to 200, 100, 50 and 25 nM TBT significantly decreased cytotoxic function 6 days later but significant activation of p38 and p44/42 by 300-50 nM TBT was realized within ten minutes of exposure. An examination of MKK3/6 and MEK1/2 also revealed activation by 300-50 and 300-100 nM TBT, respectively within ten minutes. However, when the most upstream signaling molecules in this pathway, non-receptor protein tyrosine kinases (PTKs) such as Syk, ZAP-70, Pyk2 and Src were examined, no significant activation was seen. On the other hand, no significant changes in p53 or BCL-2 family members bax and bcl-2 were seen. Taken together, these data indicate that TBT alters NK lytic granule exocytosis pathway at least at the MAP2K level causing loss of cytotoxic function and that neither pro-apoptotic proteins bax and p53 nor anti-apoptotic protein bcl-2 are changed by TBT doses that inhibit cytotoxic function. ^
Aloice O Aluoch,
"Tributyltin-induced alterations of essential signaling pathways in human natural killer cells"
ETD Collection for Tennessee State University.