Down-regulation of IL-18 receptor in cancer patients: Its clinical significance

Interleukin-18 (IL-18) is a powerful inducer of interferon-gamma (IFN-γ), a key immunoregulatory cytokine. Cellular immune responsiveness, as measured by IL-18-induced IFN-γ production from peripheral blood mononuclear cells (PBMCs) in ELISA assay, was evaluated in 10 patients with advanced cancer and in 10 normal controls. Supernatant levels of IFN-γ were detected at 2 hours after PBMCs culture and markedly increased thereafter in healthy volunteers. In contrast, IFN-γ production in cancer patients was not detected during the culture period (0-72 hours). We also measured IL-18-stimulated IL-12 production in healthy volunteers and null response was observed in cancer-bearing patients. Next, we studied mRNA expressions of IL-18 receptor (IL-18R) and IFN-γ in PBMCs in cancer patients and healthy volunteers by RT-PCR assay. Both mRNA levels of IL-18R and IFN-γ were significantly decreased in cancer-bearing patients compared with normal controls. These results suggested that IL-18 responsiveness for IFN-γ production in cancer-bearing patients was impaired. Using flow cytometric analysis, we studied T-cell subsets, CD3^- CD56⁺ (NK cell), CD3⁺ CD45RO⁺ (memory T-cell), CD3⁺ CD95⁺ (Fas⁺ T-cell), CD3⁺ CD4⁺ (helper T-cell), CD3⁺ CD8⁺ (cytotoxic T-cell: CTL) and CD3⁺ Va24⁺ (NKT-cell), in cancer patients and normal controls. The NK and cytotoxic T-cells significantly decreased and NKT-cells had decreased tendency in cancer patients compared with normal controls. In contrast, memory T-cells, Fas⁺T-cells and helper T-cells were all significantly increased in cancer patients compared with normal controls. These results suggested that the underlying mechanism of impaired IL-18 responsiveness in PBMCs from cancer-bearing patients was, at least in part, ascribed to a drastic decrease of NK cells and CTL which constitutively and highly express IL-18R and also attributed to null production of IL-12 which up-regulates IL-18R.