Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans

Eric V. Granowitz, Reuven Porat, James W. Mier, Scott F. Orencole, Gilles Kaplanski, Elizabeth A. Lynch, Ke Ye, Edouard Vannier, Sheldon M. Wolff, Charles A. Dinarello*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


When administered parenterally, endotoxin stimulates the synthesis of IL-1, TNF-α, 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 106 CD14+ cells. Six h after endotoxin injection, endotoxin-stimulated CD14+ cells synthesized 66% less IL-1β(p < 0.01), 47% less TNF-α (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-1β-induced IL-1α and TNF-α 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-1β(p = 0.06), 70% for TNF-α (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 106 PBMC, cells isolated 3 h after endotoxin injection synthesized significantly less stimulus-induced IL-1, TNF-α, 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.

Original languageEnglish
Pages (from-to)1637-1645
Number of pages9
JournalJournal of Immunology
Issue number3
StatePublished - 1 Aug 1993
Externally publishedYes


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