Suppression of Dendritic Cells by HMGB1 Is Associated with Lymph Node Metastasis of Human Colon Cancer

High mobility groupbox-1 (HMGB1) is a multifunctional cytokine secreted by cancer cells, which accelerates cell growth, invasion and angiogenesis in cancer, and induces apoptosis in macrophages. Thioglycolate-stimulated mouse peritoneal macrophages were induced to differentiate into dendritic cells by co-treatment with IL-4 and GM-CSF. The number of mouse peritoneal macrophage-derived dendritic cells (PMDDCs) showed a dose-dependent decrease in hrHMGB1 treatment. HMGB1-treated PMDDCs showed obvious apoptosis and increased the level of phosphorylated JNK. Intraperitoneal administration of HMGB1 decreased CD205-positive splenic dendritic cells in C57BL mice. To confirm the HMGB1-induced inhibitory effect on dendritic cells, 16 cases of human colon cancer invaded into the subserosal layer were examined. The 8 nodal metastasis-positive cases showed higher nodal HMGB1 concentrations (74 +/- 23 vs. 41 +/- 15 microg/ml, p = 0.0116) in lymph node tissues and lower CD205-positive nodal dendritic cell numbers (86 +/- 22 vs. 137 +/- 43/mm(2), p = 0.0224) than those in the 8 metastasis-negative cases. Primary tumor tissues of metastasis-positive cases showed higher tumor HMGB1 levels (116 +/- 33 vs. 37 +/- 18 microg/ml, p = 0.0007) and lower CD205-positive intratumoral dendritic cell numbers (21 +/- 13 vs. 62 +/- 23 /mm(2), p = 0.0068) than those in metastasis-negative cases. These findings suggest that HMGB1 produced by colon cancer cells suppressed nodal dendritic cells to disturb host anti-cancer immunity.