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 integrin VLA-4 (alpha4beta1). We investigated the signalling pathways through which this adhesive interaction might be regulated. The protein tyrosine kinase inhibitors genistein and methyl 2,5-dihydroxycinnamate (MDHC) markedly inhibited the adhesion of AK-T cells to MCA-38 cells. Furthermore, pretreatment of the AK-T cells alone (but not the MCA-38 targets) with MDHC inhibited 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 phosphatidylinositol 3-kinase inhibitor wortmannin failed to alter AK-T cell adhesion to MCA-38 tumour cells. Inhibition of protein kinase A with the Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate had no effect on adhesion, but the adenylyl cyclase activator forskolin and the cell-permeable cAMP analogues 8-Br-cAMP and dibutyryl-cAMP significantly suppressed adhesion. Pretreatment of AK-T cells alone with forskolin also inhibited adhesion. The adhesion of AK-T cells to MCA-38 tumour targets is therefore promoted by protein tyrosine kinases and protein kinase C, but inhibited by cAMP-dependent pathways, and the predominant location of the regulatory pathways is within the effector cell.
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
W M
WM
MacKenzie
D W
DW
Hoskin
J
J
Blay
D000230:Adenocarcinoma / Q000201:enzymology / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000201:enzymology / Q000276:immunology*; D000242:Cyclic AMP / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C058819:calphostin C