LPAM-1 (INTEGRIN ALPHA-4-BETA-7)-LIGAND BINDING - OVERLAPPING BINDING-SITES RECOGNIZING VCAM-1, MADCAM-1 AND CS-1 ARE BLOCKED BY FIBRINOGEN, A FIBRONECTIN-LIKE POLYMER AND RGD-LIKE CYCLIC-PEPTIDES

The alpha 4 integrin LPAM-1 (alpha 4 beta 7) mediates lymphocyte attac hment within the extracellular matrix (ECM) by adhering to the connect ing segment (CS)-1 site of fibronectin (FN). Here we reveal that very late antigen (VLA)-4(-) LPAM-1(+) T cell lymphoma TK-1 cells bind via LPAM-1 to multiple copies of the RGD sequence engineered within an FN- like polymer. Further, the small conformationally restrained RGD-like cyclic peptides 1-adamantaneacetyl-Cys-Gly-Arg-Gly-Asp-Ser-Pro-Cys and Arg-Cys-Asp-thioproline-Cys inhibit the adhesion of TK-1 cells to imm obilized CS-1 peptide, and to endothelial counterreceptors for LPAM-1, namely mucosal addressin cell adhesion molecule (MAdCAM)-1 and vascul ar cell adhesion molecule (VCAM)-1. Spontaneous adhesion of the VLA-4( -) LPAM-1(+) B lymphoma cell line RPMI 8866 to CS-1 was likewise inhib ited, confirming a previously undocumented ability of LPAM-1 to recogn ize the RGD tripeptide. The RGD-binding site in LPAM-1 either overlaps or is identical to sites required for interaction with MAdCAM-1, VCAM -1, and the CS-1. The binding of LPAM-1 and VLA-4 to RGD-containing li gands may have relevance in vivo given that fibrinogen at physiologica l concentrations is able to partially block the binding of TK-I cells to MAdCAM-1. Hence fibrinogen and other vascular RGD-containing protei ns may have mild anti-inflammatory activity required for maintaining e ffective homeostasis, analogous to the anti-thrombogenic activity of t he vascular endothelium.