33, 34 Our results demonstrate that several features of B-lymphocyte interactions with HSECs are maintained in lymphomas, including the requirement for endothelial activation by proinflammatory cytokines and a preserved role for integrin-mediated firm adhesion

MK0683 ic50 under flow. Interestingly, ICAM-1, but not VCAM-1, was involved in capturing the CRL-2261 cell line, whereas VCAM-1 predominated with the Karpas 422 line. Furthermore, the CRL-2261 cell line demonstrated higher motility on ECs, which was also ICAM-1 mediated. Detailed analysis demonstrated that the migratory capabilities of the lymphoma cell lines on the surface of the HSECs overlapped with properties observed in primary lymphocytes. We

noted shape change and motility of CRL-2261 cells on the endothelium under flow, and this migration was completely inhibited by ICAM-1 blockade. However, Karpas 422 cells did not display crawling on the endothelium under flow. We excluded the possibility that these cells are unable to migrate because they showed a marked chemotactic response to CXCL12, which has been demonstrated to be a chemoattractant factor for follicular center lymphoma, CLL, and lymphoblastic leukemia.34-37 After stable arrest, leukocytes undergo intravascular crawling and transendothelial migration across endothelial barriers into tissue. To our surprise, we found that the lymphoma cell lines were unable to undergo transendothelial transmigration under flow on HSECs. Even supplementation of the chemokine signal LDK378 ic50 with exogenous CXCL12 failed to induce transendothelial migration, despite inducing shape change. Furthermore, blocking cell division with mitomycin C did not promote transmigration. Thus, it appears that these malignantly transformed cells have lost the ability to transmigrate through triclocarban the sinusoidal endothelium. If so, this could explain why hepatic lymphomas are often associated with a sinusoidal infiltration pattern in which the malignant cells are observed to remain within the sinusoidal

channels (Fig. 4F).8 To confirm our findings in lymphoma cell lines, we studied circulating populations of primary malignant lymphocytes from patients with CLL and MZL. In keeping with the cell-line data, primary malignant cells were able to adhere to human HSECs using ICAM-1 or VCAM-1, but were unable to transmigrate across HSECs. In conclusion, we have demonstrated the molecular mechanisms involved in primary B-cell recruitment by the hepatic sinusoidal endothelium, and that these molecules could be potential therapeutic targets for chronic inflammatory liver disease. Certain aspects of lymphocyte homing are maintained in lymphoma recruitment to the liver, suggesting that therapeutic targets for lymphocyte recruitment may also prevent lymphoma dissemination to the liver.