In addition, LSLs that had interacted with tumor-activated LSECs in vivo decreased their antitumor cytotoxicity and interferon (IFN)-gamma secretion while they increased IL-10 release ex vivo. IFN-gamma/IL-10 ratio also decreased in the hepatic blood from tumor-injected mice. Immunosuppressant effects of tumor-activated LSECs on LSLs were abrogated in both LSECs from ManR−/− mice and tumor-activated LSECs

given anti-mouse ManR antibodies. Conclusion: ICAM-1–induced tumor COX-2 decreased antitumor activity during hepatic metastasis through Proteasome assay IL-1–induced ManR. ManR constituted a common mediator for prometastatic effects of IL-1, COX-2, and ICAM-1. A rise in hepatic IFN-gamma/IL-10 ratio and antitumor cytotoxicity by way of ManR blockade is consistent with the antimetastatic effects of IL-1, COX-2, and ICAM-1 inhibitors. These data support ManR and ManR-stimulating factors as targets for hepatic colorectal metastasis

therapy. Hepatology 2010;51:2172–2182 The specific blockade of major proinflammatory cytokines inhibits experimental hepatic metastasis, suggesting that inflammation-dependent mechanisms have prometastatic effects.1, 2 However, because inflammatory mediators also play an important role in the regulation of antitumor activity, the connection between inflammation and cancer progression3 deserves further attention. In 上海皓元医药股份有限公司 the liver, interleukin (IL)-1 up-regulates the endocytic activity of the RAD001 in vivo mannose receptor (ManR) expressed by liver sinusoidal endothelial

cells (LSECs).4, 5 ManR mediates uptake of glycoconjugates carrying mannose in an end position.6 Interestingly, this receptor uses a different binding domain to take up blood-borne collagen alpha chains,7, 8 and contributes to the adhesion of cancer cells to LSECs.9-11 Furthermore, ManR is involved in antigen uptake, processing, and presentation to T cells by LSECs,12 and it has been suggested that this process diminishes local immune response of the liver.13 However, it is not known how ManR is regulated during the hepatic microvascular infiltration of cancer cells. Furthermore, the contribution of ManR to antitumor defense mechanisms during hepatic metastasis is also unknown. Based on the inflammatory status of tumor-infiltrated hepatic sinusoids and the inflammatory regulation of hepatic ManR-mediated endocytosis, we hypothesized that IL-1–induced ManR-mediated endocytosis might contribute to prometastatic effects of tumor-activated LSECs via antitumor activity inhibition. This would be consistent with our previous observations demonstrating that experimental hepatic metastasis is promoted by IL-1,1, 9 that ManR-mediated endocytosis is up-regulated by this cytokine,4, 5 and that ManR-mediated LSEC activation increases metastasis through IL-1.