Inhibition of lytic function of human NK cells by Tributyltin: Role of Protein Kinase C

Abstract

Protein kinase C (PKC) catalyzes the phosphorylation of serine/threonine residues and is involved in signal transduction associated with cell proliferation, differentiation, and apoptosis. The environmental pollutant, tributyltin chloride (TBT) has been reported to decrease human Natural killer (NK) cell lytic function. We previously showed that TBT induces activation of MAPK in NK cells. In the present study, we examined the role of PKC in TBT‐ induced inhibition of NK lysis of tumor cells and TBT‐induced activation of MAPKs by using a PKC inhibitor. A 1 h treatment with Bisindolylmaleimide I caused 85% decrease in the ability of NK cells to lyse K562 tumor cells in a 2‐h 51Cr‐release assay. Western blot analysis using an antibody to phospho‐MAPKs showed that Bisindolylmaleimide I was able to completely block TBT‐induced activation of p44/42 whereas activation of p38 and JNK were not blocked. However, when the activation of PKC was blocked by the presence of Bisindolylmaleimide I, subsequent exposure to TBT produced even greater inhibition of lytic function of NK cells than was seen with TBT alone. These results indicate the pivotal role of PKC in the TBT‐induced activation of p44/42 in NK cells, possibly by activating Raf ‐> MEK ‐> MAPKs and suggest the negative effect of TBT in NK lytic function was not prevented even when the activation of PKC was blocked.