Inhibition of the transendothelial migration of human lymphocytes but not monocytes by phosphodiesterase inhibitors.
This study describes an in vitro model of peripheral blood mononuclear cell (PBMC) migration through human endothelial cells, held on polycarbonate inserts, which allows automatic differential counting of migrated cells as lymphocytes and monocytes. Using this system it was found that treatment of PBMC with the phosphodiesterase (PDE) inhibitors theophylline (at 1 and 10 micrograms/ml) and RO-20-1724 (at 1 microM) inhibited the migration of the lymphocyte component to 64.2+/-16.4%, 48.9+/-3.0% and 47.5+/-5.8% of the control values, respectively, while the migration of the monocytes component was largely unaffected. The PDE inhibitors needed to be present during the assay to inhibit migration, whereas pre-treatment of either the endothelium or the PBMC did not consistently effect lymphocyte migration. The drugs also inhibited the migration of lymphocytes through control inserts, either uncoated or coated with fibronectin, suggesting that some of the inhibition is an effect on lymphocyte motility rather than lymphocyte-endothelial interactions. Lymphocyte migration through fibronectin-coated filters was significantly enhanced compared with uncoated filters. Activation of the PBMC by anti-CD3 MoAb increased motility and migration by up to 300%. This migration appeared to be greatly inhibited by the PDE inhibitors, although the effect was complicated by problems of lymphocyte aggregation. This study provides a novel method of measuring mononuclear cell transendothelial migration, and suggests a possible role of PDE inhibitors in reducing this progress.
Lidington
E
E
Heart Science Centre, National Heart and Lung Institute at Harefield Hospital, Harefield, UK.
Nohammer
C
C
Dominguez
M
M
Ferry
B
B
Rose
M L
ML
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology* / Q000201:enzymology; D009000:Monocytes / Q000166:cytology* / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology
D005353:Fibronectins; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D013806:Theophylline