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

• Published in: Anticancer research Vol. 21; no. 5; p. 3285
• Main Authors: Kobashi, K, Iwagaki, H, Yoshino, T, Morimoto, Y, Kohka, H, Kodama, M, Nishibori, M, Akagi, T, Tanaka, N
• Format: Journal Article
• Language: English
• Published: Greece 01-09-2001
• Subjects: Adult; Aged; Down-Regulation; Female; Flow Cytometry; Humans; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interleukin-12 - biosynthesis; Interleukin-18 - pharmacokinetics; Interleukin-18 - pharmacology; Interleukin-18 Receptor alpha Subunit; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lymphocyte Subsets; Male; Middle Aged; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - genetics; Receptors, Interleukin - metabolism; Receptors, Interleukin-18; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology
• ISSN: 0250-7005

Interleukin-18 (IL-18) is a powerful inducer of interferon-gamma (IFN-gamma), a key immunoregulatory cytokine. Cellular immune responsiveness, as measured by IL-18-induced IFN-gamma 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-gamma were detected at 2 hours after PBMCs culture and markedly increased thereafter in healthy volunteers. In contrast, IFN-gamma 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-gamma in PBMCs in cancer patients and healthy volunteers by RT-PCR assay. Both mRNA levels of IL-18R and IFN-gamma were significantly decreased in cancer-bearing patients compared with normal controls. These results suggested that IL-18 responsiveness for IFN-gamma 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+ V alpha24+ (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.