Endotoxin Tolerance after Severe Injury and Its Regulatory Mechanisms

Objective : To study the responsiveness of peripheral blood mononuclear cells to lipopolysaccharide (LPS) after severe trauma and its regulatory mechanisms. Materials and Methods : The release of proinflammatory reacting cytokines (tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, interferon (IFN)-γ) into whole blood from 12 patients on day 1, 5, 10, and 14 after severe trauma (Injury Severity Score, 39.3 ± 2.8 points) and 10 healthy volunteers was studied after stimulation with LPS, concanavalin A, phorbol myristate acetate (PMA), and the addition of recombinant IFN-γ. Main Results : Trauma caused a significant reduction of LPS and concanavalin A induced release of inflammation activating cytokines into whole blood, including IFN-γ. However, the diminished release of proinflammatory cytokines could be increased with recombinant IFN-γ or even attenuated after stimulation of peripheral blood mononuclear cells with the protein kinase C activator PMA. Conclusions : Trauma leads to reduced responsiveness of blood monocytes to LPS and a decreased secretion of proinflammatory reacting lymphokines. Because activation of the protein kinase C pathway with PMA or the addition of IFN-γ significantly increased cytokine response, endotoxin tolerance is not caused by inhibition of protein synthesis, but to disturbances in the signal transduction pathway and its regulating mediators.