Abstract. Leukocyte interactions with vascular endothelium at sites of inflammation can be dynamically regulated by activation-dependent adhesion molecules. Current models, primarily based on studies with polymorphonuclear leukocytes, suggest the involvement of multiple members of the selectin, integrin, and immunoglobulin gene families, sequentially, in the process of initial attachment (rolling), stable adhesion (arrest), spreading and ultimate diapedesis. In the current study, IL-4-activated human umbilical vein endothelium, which selectively expresses VCAM-1 and an L-selectin ligand but not E-selectin, and appropriate function blocking monoclonal antibodies, were used to study monocyte-endothelial interactions in an in vitro model that mimics microcirculatory flow conditions. In this system, L-selectin mediates monocyte rolling and also facilitates ouBl-integdn-dependent arrest, whereas/~-integrins are required for spreading of firmly attached monocytes on the endothelial cell surface but not their arrest. These findings provide the first in vitro evidence for human monocyte rolling on cytokine-activated endothelium, and suggest a sequential requirement for both/~1-and/~2-integfin-dependent adhesive mechanisms in monocyte-endothelial interactions.p ERIPHERAL blood monocytes interact with the vascular endothelial lining as an initial step in a wide range of pathological processes including acute and chronic inflanunation, immune reactions, and atherosclerosis (12,13,45). As a consequence of their transendothelial migration, monocytes are recruited into tissues, organs and body cavities, undergo maturation to macrophages, and participate in defending the host against invading pathogens and regulating the behavior of vascular and non-vascular cells through the secretion of cytokines and other chemical mediators.Early in vitro studies of monocyte adhesion to cultured endothelial cells were typically performed under static conditions and indicated that basal adhesion of purified blood monocytes was relatively high

S nlTln'lary L-selectin, a cell surface adhesion molecule that is expressed by most leukocytes, mediates leukocyte rolling along vascular endothelium at sites of inflammation. The contribution of L-selectin to leukocyte migration in models of chronic inflammation was assessed by using mice that lack cell surface L-selectin expression. Significant inhibition of neutrophil (56-62%), lymphocyte (70-75%), and monocyte (72-78%) migration into an inflamed peritoneum was observed 24 and 48 h after administration of thioglycollate, an inflammatory stimulus. L-selectin-deficient mice were also significantly impaired in delayed-type hypersensitivity reactions. Footpad swelling in response to sheep red blood cell challenge was reduced 75% in I~selectin-deficient mice compared with wild-type mice. Ear swelling in a model of contact hypersensitivity induced by oxazolone challenge was also reduced by 69% compared to wild-type mice. Consistent with bselectin-mediating leukocyte migration into diverse vascular beds during inflammation, L-selectin-deficient mice were significantly resistant to death resulting from lipopolysaccharide (LPS)-induced toxic shock. LPS administration resulted in a 90% mortality rate in control mice after 24 h, while there was a 90% survival rate in L-selectin-deficient mice. These results demonstrate that L-selectin plays a prominent role in leukocyte homing to nonlymphoid tissues during inflammation and that blocking this process can be beneficial during pathological inflammatory responses.

SUMMARYThe adhesion molecule L-selectin (CD62L) mediates lymphocyte recirculation and leucocyte rolling on vascular endothelium at sites of inflammation. Serum levels of soluble L-selectin (sL-selectin) were measured in patients with SLE in order to relate these levels to clinical activity and immunological parameters. An ELISA was used to detect the soluble form of human L-selectin (CD62L) in 42 patients with SLE and in 33 healthy individuals. The mean Ϯ s.e.m. values of sL-selectin were 1285 Ϯ 121 ng/ml for patients with SLE and 986 Ϯ 180 ng/ml for healthy blood donors, but there was no significant difference. When patients with active SLE were analysed, higher levels of circulating sL-selectin were found when compared with patients without activity (1497 Ϯ 167 ng/ml versus 941 Ϯ 150 ng/ml; P ¼ 0·028). We found a significant correlation between the levels of sL-selectin and of dsDNA antibodies (r ¼ 0·36, P ¼ 0·044) and between levels of sL-selectin and SLE Disease Activity Index (SLEDAI) score (r ¼ 0·42, P ¼ 0·003). Patients with active SLE studied cross-sectionally showed significant elevations of sL-selectin (CD62L) compared with controls. Thus, the levels of this soluble adhesion molecule correlated with active disease and levels of anti-dsDNA antibodies.

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