Effects of Triphenyltin Chloride TPTC on Human NK Cell Function

7 Effects of Triphenyltin Chloride (TPTC) on Human NK Cell Function 

Exposure of NK cells for 1 h to 1, 0.5 and 0.2 pM TPTC caused decreases in NK lytic function of 95%, 84%, and 31% (Table 4.5.7). After a 48 h exposure to 0.2 pM TPTC, lysis was inhibited by 94%. A 6 d exposnre to TPTC cansed a decrease in lytic function of 38 27% at 0.05 pM (Table 4.5.7). ° In addition we have shown that a 1 h exposnre to TPTC caused a persistent loss of lytic function, as was seen with TBTC and DBTC (Table 4.5.7). ° 

In order for NK cells to lyse their targets, including tumor cells, the NK cell must bind to the target utilizing cell surface proteins present on the NK cell, as well as on the target. We found that each of the OTs is able to decrease the ability of NK cells to bind to their targets. However, this decrease is a slower consequence of OT exposure than is the decrease in lytic function. 

One consequence of NK cell exposure to OT that occurs quickly (within 10 minutes) is an increase in the activation of mitogen-activated protein kinases (MAPK). These enzymes are critical to the function of the NK cells, as well as nearly all other cell types. TBTC can significantly activate MAPKs within 10 min of exposure and this activation can be accounted for by TBTC-induced activation of the immediate upstream activators of MAPKs, referred to as MAPK kinases (MAP2Ks). Activation of MAPKs by TBTC would leave the NK cell unable to respond to target cells when they were encountered. The activation of the MAPK pathway by OT exposure occurs within a timeframe that could account for the loss of lytic function seen at exposures of less than 48 h, while the other alterations such as ATP decreases and binding decreases take longer to occur. We have unpublished data indicating that DBTC is also able to increase MAPK activity in NK cells within 10 min. Thus, it will be important to examine the other OTs to determine if this is a common mechanism in the OT-induced inhibition of NK lytic function. 

Finally, a series of OTs that differed in their lipophilicity (TMTC, DMPTC, MDPTC, and TPTC) has been shown to decrease the lytic function of NK cells in the order TMTC DMPTC MDPTC TPTC. These results indicate that an increase in the lipophilic nature of the OTs appears to increase their immunotoxicity. 

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