IL-1 activation of endothelium supports VLA-4 (CD49d/CD29)-mediated monocyte transendothelial migration to c5a, MIP-1α, RANTES, and PAF but inhibits migration to MCP-1: A regulatory role for endothelium-derived MCP-1

We investigated the effect of interleukin-1 (IL-1) activation of human umbilical vein endothelium (HUVE) on human monocyte transendothelial migration induced by chemotactic factors. Monocyte migration across unactivated endothelium in response to macrophage inflammatory protein-1α (MIP-1α), RANTES, platelet-activating factor (PAF), or monocyte chemoattractant protein-1 (MCP-1) was completely inhibited (90%) by monoclonal antibodies (mAbs; 60.3) to CD18 of the CD11/CD18 complex on the monocyte and partially inhibited (by 75%) in response to C5a. When the HUVE was stimulated with IL-1α (5 h, 0.1 ng/ml), monocyte migration in response to C5a, MIP-1α, RANTES, or PAF was no longer inhibited by mAb to CD18. However, migration was blocked by the combination of mAb to the α₄-integrin (CD49d) chain of very late antigen-4 (CD49d/CD29) with the mAb to CD18. In contrast to the above stimuli, activation of the HUVE with IL-1α inhibited the transendothelial migration of monocytes in response to MCP-1. mAbs to the adhesion molecules up-regulated on HUVE by IL-1, i.e,, E-selectin (CD62E), intercellular adhesion molecule-1 (CD54) or vascular cell adhesion molecule-1 (CD106), did not reverse the inhibitory effect. Transendothelial migration in response to MCP-1 but not to C5a was inhibited by the treatment of monocytes with culture supernatant from IL-1α-stimulated (but not from unstimulated) HUVE. Such supernatant contained chemotactic activity for monocytes, and a mAb to MCP-1 blocked the migration inhibitory effect of IL-1 activation of the HUVE monolayer, as well as the chemotactic activity in the supernatant from IL-1-stimulated HUVE. The inhibitory effect on migration of IL-1-stimulated HUVE was specific for monocytes because polymorphonuclear leukocyte transendothelial migration in response to IL-8 (a related chemokine) was not inhibited by IL-1 activation of HUVE, These results demonstrate that: (1) C5a but not MCP-1, MIP-1α, RANTES, or PAF activates not only a CD18-dependent but also a VLA-4-dependent mechanism on monocytes, which mediates migration across unstimulated HUVE; (2) IL-1 (tumor necrosis factor a or lipopolysaccharide) activation of HUVE results in efficient VLA-4 (CD49d/CD29)mediated monocyte transendothelial migration in response to C5a, RANTES, MIP-1α, and PAF, in addition to the CD18-dependent pathway, but inhibits the response to MCP-1; and (3) this selective inhibition is probably due to MCP-1 production by the activated endothelium monolayer and may be one mechanism of downregulation by the endothelium of monocyte migration in response to extravascular MCP-1.