title: Down-regulation of IL-18 receptor in cancer patients: its clinical significance.
abstract: 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.
authors.affiliation: First Department of Surgery, Okayama University Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kobashi
authors.forename: H
authors.initials: H
authors.lastname: Iwagaki
authors.forename: T
authors.initials: T
authors.lastname: Yoshino
authors.forename: Y
authors.initials: Y
authors.lastname: Morimoto
authors.forename: H
authors.initials: H
authors.lastname: Kohka
authors.forename: M
authors.initials: M
authors.lastname: Kodama
authors.forename: M
authors.initials: M
authors.lastname: Nishibori
authors.forename: T
authors.initials: T
authors.lastname: Akagi
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D000368:Aged; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000493:pharmacokinetics / Q000494:pharmacology; D053727:Interleukin-18 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D016131:Lymphocyte Subsets; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053724:Receptors, Interleukin-18; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma