title: Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans.
abstract: When administered parenterally, endotoxin stimulates the synthesis of IL-1, TNF-alpha, and IL-6. However, this initial injection induces tolerance; a second injection of endotoxin results in lower levels of circulating cytokines. In our study, five healthy male volunteers between the ages of 18 and 30 were injected with Escherichia coli endotoxin. Four subjects received only saline. Immediately before the injection and 3, 6, and 24 h afterward, PBMC were isolated and stimulated in vitro with endotoxin, IL-1, or toxic shock syndrome toxin-1. Inasmuch as CD14+ monocytes are the primary source of the cytokines induced by these stimuli, results are expressed as cytokine production per 10(6) CD14+ cells. Six h after endotoxin injection, endotoxin-stimulated CD14+ cells synthesized 66% less IL-1 beta (p < 0.01), 47% less TNF-alpha (p < 0.001), 56% less IL-6 (p < 0.01), and 49% less IL-8 (p < 0.01) than cells obtained before the injection. This suppression was not specific for endotoxin; IL-1 beta-induced IL-1 alpha and TNF-alpha were reduced by 84% (p = 0.01) and 68% (p < 0.001), respectively. A decrease in cytokine synthesis was also observed using toxic shock syndrome toxin-1 as a stimulus: 57% for IL-1 beta (p = 0.06), 70% for TNF-alpha (p < 0.01), 56% for IL-6 (p < 0.05), and 71% for IL-8 (p = 0.001). When data were expressed as cytokine production per 10(6) PBMC, cells isolated 3 h after endotoxin injection synthesized significantly less stimulus-induced IL-1, TNF-alpha, IL-6, and IL-8 than did PBMC from saline-injected controls. We conclude that endotoxin tolerance is due, in part, to changes in the stimulus-induced cytokine response of circulating CD14+ cells.
authors.affiliation: Department of Medicine, New England Medical Center Hospital, Boston, MA 02111.
authors.forename: E V
authors.initials: EV
authors.lastname: Granowitz
authors.forename: R
authors.initials: R
authors.lastname: Porat
authors.forename: J W
authors.initials: JW
authors.lastname: Mier
authors.forename: S F
authors.initials: SF
authors.lastname: Orencole
authors.forename: G
authors.initials: G
authors.lastname: Kaplanski
authors.forename: E A
authors.initials: EA
authors.lastname: Lynch
authors.forename: K
authors.initials: K
authors.lastname: Ye
authors.forename: E
authors.initials: E
authors.lastname: Vannier
authors.forename: S M
authors.initials: SM
authors.lastname: Wolff
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001427:Bacterial Toxins; D017252:CD3 Complex / Q000032:analysis; D019002:CD56 Antigen; D016207:Cytokines / Q000096:biosynthesis*; D004731:Endotoxins / Q000494:pharmacology*; D004768:Enterotoxins / Q000494:pharmacology; D004926:Escherichia coli / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007375:Interleukin-1 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors; D008297:Male; D018089:Superantigens
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000945:Antigens, Differentiation, T-Lymphocyte; D001427:Bacterial Toxins; D017252:CD3 Complex; D019002:CD56 Antigen; D016207:Cytokines; D004731:Endotoxins; D004768:Enterotoxins; D007375:Interleukin-1; D018950:Lipopolysaccharide Receptors; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal