Thiopental inhibits the activation of nuclear factor kappaB.
BACKGROUND
Thiopental is frequently used for the treatment of intracranial hypertension after severe head injury. Its long-term administration increases the incidence of nosocomial infections, which contributes to the high mortality rate of these patients. However, the mechanism of its immunosuppressing effect remains unknown.


METHODS
The effect of thiopental (200-1000 microg/ml) on the activation of the nuclear transcription factor kappaB (NF-kappaB; electrophoretic mobility shift assays), on NF-kappaB-driven reporter gene activity (transient transfection assays), on the expression of NF-kappaB target genes (enzyme-linked immunoassays), on T-cell activation (flow cytometric analyses of CD69 expression), and on the content of the NF-kappaB inhibitor IkappaB-alpha (Western blotting) was studied in human T lymphocytes in vitro.


RESULTS
Thiopental inhibited the activation of the transcription factor NF-kappaB but did not alter the activity of the cyclic adenosine monophosphate response element binding protein. Other barbiturates (methohexital), anesthetics (etomidate, propofol, ketamine), or opioids (fentanyl, morphine) did not affect NF-kappaB activation. Thiopental-mediated suppression of NF-kappaB could be observed in Jurkat cells and in primary CD3+ lymphocytes from healthy volunteers, was time- and concentration-dependent, occurred at concentrations that are clinically achieved, and persisted for hours after the incubation. It was associated with an inhibition of NF-kappaB-driven reporter gene activity, of the expression of interleukin-2, -6, and -8, and interferon gamma, and of the activation of CD3+ lymphocytes. Suppression of NF-kappaB appeared to involve reduced degradation of IkappaB-alpha.


CONCLUSIONS
The results demonstrate that thiopental inhibits the activation of NF-kappaB and may thus provide a molecular mechanism for some of the immunosuppressing effects associated with thiopental therapy.
Loop
Torsten
T
Department of Anesthesiology, University Hospital, Freiburg, Germany.
Liu
Zhiheng
Z
Humar
Matjaz
M
Hoetzel
Alexander
A
Benzing
Albert
A
Pahl
Heike L
HL
Geiger
Klaus K
KK
J  Pannen
Benedikt H
BH
D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D004586:Electrophoresis; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007202:Indicators and Reagents; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013874:Thiopental / Q000494:pharmacology*
D016207:Cytokines; D006993:Hypnotics and Sedatives; D007202:Indicators and Reagents; D016328:NF-kappa B; D013874:Thiopental