A postulated paradigm of TM–leukocyte interactions. Under quiescent conditions (A), endothelial TM is intact. Its lectin-like domain binds to whatever Le^y is exposed by endothelial glycoproteins, blocking Le^y interactions with TM expressed by circulating leukocytes, thereby preventing leukocyte adhesion. During inflammatory conditions (B), endothelial cells become activated. TM expression is reduced, and various fragments of the ectodomain of TM are released (only a couple are shown schematically) into the circulation (red arrows) by proteolytic cleavage of the membrane-bound form. Remaining EGF4-EGF5 is oxidized, diminishing the generation of APC (not shown). ICAM-1, VCAM-1, and Le^y expression on glycoproteins is increased on the endothelial cell surface. Le^y binds to the lectin-like domain of TM expressed by activated leukocytes, which induces activation of leukocyte β2-integrins (β2-ITG). These bind to endothelial cell adhesion molecules ICAM-1 and VCAM-1, enabling firm leukocyte adhesion and transmigration. Exposed by proteolysis of the intact protein, the serine-threonine–rich region of TM provides a binding site, likely via the chondroitin sulfate, for leukocyte-expressed adhesion molecules LFA-1 and MAC-1, further promoting leukocyte-endothelial cell attachment and inflammation. Therapeutic recombinant TM comprising the entire ectodomain, or the lectin-like domain alone, or the EGF-like region plus the serine-threonine rich region (TMD23), exhibit anti-inflammatory properties by blocking leukocyte-endothelial interactions. LLD, lectin-like domain.