VASCULAR CELL-ADHESION MOLECULE-1 EXPRESSED BY PERITONEAL MESOTHELIUMPARTLY MEDIATES THE BINDING OF ACTIVATED HUMAN T-LYMPHOCYTES

Adhesion molecules such as selectins and integrins are known to mediat e leukocyte attachment and transmigration through activated vascular e ndothelium. However, the molecules that mediate subsequent leukocyte e ntry into nonvascular spaces such as the abdominal cavity during state s of peritoneal inflammation have not been identified. Because the per itoneal mesothelial lining represents the final barrier to leukocyte m igration into the abdomen, it is likely that adhesion molecules expres sed by mesothelial cells are involved in this process. We have develop ed an in vitro binding assay using confluent layers of normal human me sothelial cells to determine which adhesion molecules might be involve d in T lymphocyte-mesothelial recognition. Normal peripheral blood T l ymphocytes exhibit low-level specific binding to mesothelium (mean 13% specific binding, n=4), which is enhanced by phorbol myristate acetat e (PMA) treatment (mean 38% specific binding, n=4). This binding is si gnificantly inhibited in the combined presence of antibodies reactive with CD29 and CD18, suggesting a role for beta 1 and beta 2 integrins, respectively, in this interaction. Interestingly, cultured human meso thelial cells were shown to express vascular cell adhesion molecule-1 (VCAM-1), suggesting that this molecule might function as a counter-re ceptor for alpha 4 beta 1 expressed by T lymphocytes. Mesothelial cell s were also noted to express ICAM-1, CD29, and CD44, but not CD18 or s electins. VCAM-1 expression was not a constitutive property of freshly obtained mesothelial cells but was inducible upon culture in the pres ence of either interleukin-l (IL-1), tumor necrosis factor (TNF), or P MA. Neutralizing antibodies reactive with either alpha 4, VCAM-1, or C D29 were all equally capable of inhibiting the binding of activated le ukocytes to mesothelial cells (in the presence of anti-CD18 antibody). Mesothelial VCAM-1 was found to have a molecular mass of 110 kD and a n mRNA transcript of approximate to 3.2 kb, consistent with the predom inant VCAM-1 species found in activated endothelium. These data sugges t that functional VCAM-1 is expressed on activated mesothelial cells a nd may play a role in the distal arm of leukocyte trafficking to the a bdominal cavity.