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.


METHODS
The release of proinflammatory reacting cytokines (tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-8, interferon (IFN)-gamma) 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-gamma.


RESULTS
Trauma caused a significant reduction of LPS and concanavalin A induced release of inflammation activating cytokines into whole blood, including IFN-gamma. However, the diminished release of proinflammatory cytokines could be increased with recombinant IFN-gamma 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-gamma 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.
Keel
M
M
Division of Trauma Surgery, University Hospital Zurich, Switzerland.
Schregenberger
N
N
Steckholzer
U
U
Ungethüm
U
U
Kenney
J
J
Trentz
O
O
Ertel
W
W
D000293:Adolescent; D000328:Adult; D000368:Aged; D016207:Cytokines / Q000096:biosynthesis*; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009104:Multiple Trauma / Q000276:immunology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma