The adhesion of anti-CD3-activated mouse T cells to syngeneic colon adenocarcinoma cells is differentially regulated by protein tyrosine kinase-, protein kinase C-, and cAMP-dependent pathways in the effector cell

The adhesion of anti-CD3-activated mouse T cells (AK-T cells) to syngeneic colon adenocarcinoma (MCA-38) cells is mediated principally through the int egrin VLA-4 (alpha(4)beta(1)), We investigated the signalling pathways thro ugh which this adhesive interaction might be regulated. The protein tyrosin e kinase inhibitors genistein and methyl 2,5-dihydroxycinnamate (MDHC) mark edly inhibited the adhesion of AK-T cells to MCA-38 cells. Furthermore, pre treatment of the AK-T cells alone (but not the MCA-38 targets) with MDHC in hibited adhesion to a comparable extent as when MDHC was present during the assay. Calphostin C, an inhibitor of protein kinase C, also inhibited the adhesion of AK-T cells to MCA-38 monolayers. However, the phosphatidylinosi tol 3-kinase inhibitor wortmannin failed to alter AK-T cell adhesion to MCA -38 tumour cells. Inhibition of protein kinase A with the R-p diastereomer of adenosine cyclic 3',5'-phosphorothioate had no effect on adhesion, but t he adenylyl cyclase activator forskolin and the cell-permeable cAMP analogu es 8-Br-cAMP and dibutyryl-cAMP significantly suppressed adhesion. Pretreat ment of AK-T cells alone with forskolin also inhibited adhesion. The adhesi on of AKT cells to MCA-38 tumour targets is therefore promoted by protein t yrosine kinases and protein kinase C, but inhibited by cAMP-dependent pathw ays, and the predominant location of the regulatory pathways is within the effector cell. (C) 1999 Academic Press.