title: An in vitro Shwartzman reaction-like response is augmented age-dependently in human peripheral blood mononuclear cells.
abstract: A lethal human septic shock model, mouse generalized Shwartzman reaction (GSR), was elicited by two consecutive lippolysaccharide (LPS) injections (24 h apart) in which interferon-gamma (IFN-gamma) induced by interleukin (IL)-12 played a critical role in the priming phase, and tumor necrosis factor (TNF) was an important effector molecule in the second phase. We recently reported IL-12/LPS-induced mouse GSR age-dependently enhanced. We herein demonstrate that human peripheral blood mononuclear cells (PBMC) from healthy adults/elderly, cultured with IL-12 for 24 h and with LPS for an additional 24 h, produced a much larger amount of TNF (which increased age-dependently) than did PBMC without IL-12 priming. Whereas macrophages mainly produced TNF following LPS stimulation, macrophages and lymphocytes were necessary for a sufficient TNF production. IL-12-induced IFN-gamma up-regulated Toll-like receptor 4 (TLR-4) on macrophages of adults. Although the PBMC from children produced a substantial amount of IFN-gamma after IL-12 priming, the GSR response, with augmented TNF production and an up-regulated TLR-4 expression of macrophages, was not elicited by LPS stimulation. CD56+natural killer cells, CD56+T cells, and CD57+T cells (NK-T cells), which age-dependently increased in PBMC, produced much larger amounts of IFN-gamma after IL-12 priming than that of conventional CD56-CD57-T cells and also induced cocultured macrophages to produce TNF by subsequent LPS stimulation. The elder septic patients were consistently more susceptible to lethal shock with enhanced serum TNF levels than the adult patients. The NK cells, NK-T cells, and macrophages, which change proportionally or functionally with aging, might be involved in the enhanced GSR response/septic shock observed in elderly patients.
authors.affiliation: Department of Pediatrics, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Motegi
authors.forename: Manabu
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Kengo
authors.initials: K
authors.lastname: Sato
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ono
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Hoshio
authors.initials: H
authors.lastname: Hiraide
authors.forename: Shuhji
authors.initials: S
authors.lastname: Seki
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology*; D019002:CD56 Antigen / Q000276:immunology; D018959:CD57 Antigens / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D012772:Shock, Septic / Q000276:immunology*; D012790:Shwartzman Phenomenon / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D019002:CD56 Antigen; D018959:CD57 Antigens; D016207:Cytokines; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma