INTERFERENCE OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS WITH VERY LATE ACTIVATION ANTIGEN-4 VASCULAR CELL-ADHESION MOLECULE-1-MEDIATED LYMPHOCYTE ENDOTHELIAL-CELL ADHESION

Objective. To study the effect of nonsteroidal antiinflammatory drugs (NSAIDs) on the adhesion of peripheral blood lymphocytes (PBL) to acti vated human umbilical vein endothelial cells (HUVEC) under conditions that resemble blood flow. Methods. Assays of adhesion of PBL to HUVEC off recombinant vascular cell adhesion molecule 1 (rVCAM-1), intercell ular adhesion molecule 1 (ICAM-1), and E-selectin were performed under continuous rotation at 37 degrees C, The phenotype of PBL subpopulati ons attached was characterized by flow cytometry, Lymphocytes were pre treated with different doses (5-100 mu g/ml) of aceclofenac, diclofena c, indomethacin, or piroxicam or with inhibitory monoclonal antibodies (MAb) prior to the adhesion assays. The effect of NSAIDs on lymphocyt e adhesion molecules was assessed by flow cytometry, To determine whet her NSAIDs interfere,vith the affinity state of very late activation a ntigen 4 (VLA-4) integrin, we studied the effect of these drugs on the appearance of a pi activation-dependent epitope recognized by the HUT S21 MAb both on human T lymphoblasts and on synovial fluid lymphocytes (SFL). Results. In the flow-resembling model, PEG HUVEC adhesion was mainly mediated by the VLA-4/VCAM-1 adhesion pathway. The major PBL su bset attached was the CD3+, CD45RO+ memory T cell, with CD49d(high) ex pression. Aceclofenac, diclofenac, and indomethacin, but not piroxicam , were able to inhibit PBL adhesion to HUVEC or rVCAM-1, However, the quantitative expression of VLA-4 was not affected by treatment of PBL with any of the NSAIDs studied. On T lymphoblasts and SFL, mostly CD45 RO+ cells, the expression of the beta 1 activation-dependent epitope d etected by HUTS21 MAb was significantly decreased by aceclofenac, dicl ofenac, and indomethacin. Conclusion. Some NSAIDs are able to inhibit the adhesion of PBL to HUVEC under conditions that resemble blood flow by interfering with the conformational change in VLA-4 that increases its affinity for VCAM-1.