Endotoxin tolerance is not a LPS-specific phenomenon: partial mimicry with IL-1, IL-10 and TGFβ

Abstract

Administration of non-lethal doses of lipopolysaccharide (LPS) to experimental animals and humans results for a short period of time in a state of hyporesponsiveness to a second LPS challenge. This phenomenon, known as endotoxin tolerance, has been reproduced in vitro using human monocytes, rendered endotoxin-tolerant following a first incubation with LPS. A further activation by LPS was manifested by a dramatically reduced production of tumor necrosis factor α (TNFα). We report this low responsiveness of LPS pretreated monocytes as an endotoxin non-specific phenomenon. Indeed, TNFα release upon further activation with either killed Gram-positive bacteria (Staphylococci, Streptococci) or zymosan was also significantly diminished. This was not the case when phorbol myristate acetate (PMA) was used as a second triggering agent, suggesting that the monocyte hyporesponsiveness due to LPS does not affect all activation pathways, particularly that of protein kinase C. On the other hand, both PMA and zymosan pretreatment could reduce a further activation of monocytes by LPS. We investigated whether the first signal(s) delivered by LPS, could be mimicked by some of the LPS-induced cytokines. Preincubation of monocytes with either interleukin-1 (IL-1), IL-10 or transforming growth factor β (TGFβ) lower the TNFα production upon further activation with LPS. None of the cytokines alone was as efficient as the LPS molecule, but high levels of tolerization were obtained with combination of IL-1, IL-10 and TGFβ. Neither IL-6, IL-8 nor TNFα led to hyporeactive cells. Our data indicate that endotoxin tolerance is not an LPS-specific phenomenon and that more than one cytokine can contribute to render human monocytes hyporeactive to further activation by LPS.