FUNCTIONAL REGULATION OF PLATELET ENDOTHELIAL CELL-ADHESION MOLECULE-1 BY TGF-BETA-1 IN PROMONOCYTIC U-937 CELLS/

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a widely di stributed cell adhesion molecule present on monocytes, macrophages, an d monocytic cell lines. Treatment of the promonocytic cell line U-937 with TGF-beta 1 induces homotypic cellular aggregations, simultaneous with an increase in surface expression and specific transcripts of PEC AM-1. The TGF-beta-induced cell adhesion phenomena are not dependent o n LFA-1, intercellular adhesion molecule-1 (ICAM-1), very late Ag-4 (V LA-4), or very late Ag-5 (VLA-5). However, the phenomena seem to be di rectly mediated by PECAM-1 because 1) it is inhibited by the addition of Abs or an antisense oligonucleotide specific for PECAM-1;and 2) TGF -beta 1-treated U-937 cells bind to PECAM-1-expressing mouse transfect ant fibroblasts, but not to mock transfectants. In addition, this aggr egation phenomena are divalent cation-dependent and requires the integ rity of the cytoskeleton. Analysis of the intracellular signaling path ways indicates that TGF-beta 1 induces protein kinase C activity, as w ell as PECAM-1 phosphorylation and association with cytoskeletal compo nents. Furthermore, in this model, an autocrine mechanism for releasin g the bioactive form of TGF-beta 1 operates, allowing PECAM-1 activati on. These results provide evidence that TGF-beta 1 regulates PECAM-1 f unction by increasing the expression and activating the adhesion of PE CAM-1 in monocytic cells. These two mechanisms seem to be necessary fo r adhesion because independent inhibition of either expression or acti vation of PECAM-1 leads to abrogation of cellular aggregation.