Influence of IL–1β and IL–1 receptor antagonist on T-cell adhesion to hepatic endothelial cells: a potential implication for leukocyte recruitment in HCC

Background/Aim: Lymphocyte adhesion and transmigration through endothelial cells are prerequisites for the effective enrichment of cytotoxic T-cells into the tumor during anti-tumor immune response. Cytokines produced in the tumor microenvironment influence the expression of specific adhesion molecules on endothelial cells and, therefore, modulate recruitment of immune cells into the tumor tissue. Interleukin–1β (IL–1β) is an important proinflammatory cytokine with variety of functions and interleukin–1 receptor antagonist (IL–1RN) is its natural antagonist that binds to IL–1 receptor without activating. The aim of the present study was to examine the effects of IL–1β and IL–1RN on T-cell adhesion to hepatic endothelial cells. Methods and results: We used a transgenic HCC mouse model (AlbTag). To characterize endothelial cells in vitro, we isolated hepatic sinusoidal endothelial cells and tumor endothelial cells. Cultured primary tumor and hepatic endothelial cells expressed VCAM–1, ICAM–1, CD31, LYVE–1, CD146, but not P- or E-selectins. Cytokine antibody arrays and ELISA showed that the ratio of IL–1RN/IL–1β was elevated in tumor tissue and in plasma of tumor-bearing mice. IL–1β increased expression of VCAM–1 and ICAM–1 in endothelial cells in vitro appr. 1.5 and 1.3 times, respectively. Administration of IL–1β promoted adhesion of CD4⁺ and CD8⁺ T-cells to hepatic endothelial cells (20% and 44%, respectively). The activating effect of IL–1β was completely abrogated by IL–1RN. The qRT-PCR demonstrated an elevated level of IL–1RN in 52% of human HCC tissues. Conclusion: IL–1RN is upregulated in both human and mouse HCC tissues. IL–1β activates endothelial cells adhesion molecules and promotes adhesion of CD4⁺ and CD8⁺ T-cells to hepatic sinusoidal endothelial cells in vitro, whereas IL–1RN prevents IL–1β-induced endothelium activation. The interaction between IL–1RN and IL–1β may represent an important factor in process of leukocytes recruitment in HCC.

IL-1β