Colon Carcinoma Cell Interaction With Liver Sinusoidal... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Colon Carcinoma Cell Interaction With Liver Sinusoidal Endothelium Inhibits Organ-Specific Antitumor Immunity Through Interleukin-1-Induced Mannose Receptor in Mice

Arteta, Beatriz1; Lasuen, Nerea1; Lopategi, Aritz1; Sveinbjörnsson, Baldur3,4; Smedsrφd, Bård2; Vidal-Vanaclocha, Fernando1,*

1_Department of Cellular Biology and Histology, Basque Country University School of Medicine and Dentistry, Leioa, Bizkaia, Spain_

2_Department of Cell Biology and Histology, University of Tromsφ, Tromsφ, Norway_

3_Childhood Cancer Research Unit, Karolinska Institute, Stockholm, Sweden_

4_Department of Immunology, University of Tromsφ, Tromsφ, Norway_

*Address reprint requests to: Department of Cellular Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, Bizkaia-48940, Spain. Email:[email protected]; fax: (34)- 94-601-3266

Received 30 September 2009; Accepted 19 January 2010

Published online 12 February 2010 in Wiley InterScience (www.interscience.wiley.com).

Supported by Deutsche Forschungsgemeinschaft Grant no. SFB815; ECCPS. Sander-Foundation Grant number: 2007.070.2.

Potential conflict of interest: Nothing to report.

Additional Supporting Information may be found in the online version of this article.

Abstract

Mannose receptor (ManR)-mediated liver sinusoidal endothelial cell (LSEC) endocytosis plays a role in antigen presentation and innate immunity, but its role in hepatic metastasis is unknown. We studied ManR-mediated endocytosis during C26 colorectal cancer cell interaction with LSECs and its implications in metastasis. Uptake of labeled ManR ligands (mannan and ovalbumin) and immunohistochemistry were used to study ManR endocytosis and expression. Several interleukin (IL)-1 inhibitors and the cyclooxygenase-2 (COX-2) inhibitor celecoxib were used to analyze the role of IL-1 and COX-2 in ManR regulation. Anti-mouse ManR antibodies and ManR knockout (ManR−/−) mice were used to identify ManR-dependent mechanisms during antitumor immune response of liver sinusoidal lymphocytes (LSLs) interacting with tumor-activated LSECs. ManR expression and endocytosis increased in tumor-activated LSECs through a two-step mechanism: (1) Release of COX-2–dependent IL-1–stimulating factors by lymphocyte function–associated antigen-1–expressing C26 cells in response to intercellular adhesion molecule-1 (ICAM-1), which was expressed and secreted by tumor-activated LSECs; and (2) widespread up-regulation of ManR in LSECs through tumor-induced IL-1. 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 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