Sevoflurane inhibits phorbol-myristate-acetate-induced activator protein-1 activation in human T lymphocytes in vitro: potential role of the p38-stress kinase pathway.
BACKGROUND
Modulation of immune defense mechanisms by volatile anesthetics during general anesthesia may compromise postoperative immune competence and healing reactions and affect the infection rate and the rate of tumor metastases disseminated during surgery. Several mechanisms have been suggested to account for these effects. The current study was undertaken to examine the molecular mechanisms underlying these observations.


METHODS
Effects of sevoflurane, isoflurane, and desflurane were studied in vitro in primary human CD3 T-lymphocytes. DNA-binding activity of the transcription factor activator protein-1 (AP-1) was assessed using an electrophoretic mobility shift assay. Phorbol-myristate-acetate-dependent effects of sevoflurane on the phosphorylation of the mitogen-activated protein kinases were studied using Western blots, the trans-activating potency of AP-1 was determined using reporter gene assays, and the cytokine release was measured using enzyme-linked immunosorbent assays.


RESULTS
Sevoflurane inhibited activation of the transcription factor AP-1. This effect was specific, as the activity of nuclear factor kappabeta, nuclear factor of activated T cells, and specific protein-1 was not altered and several other volatile anesthetics studied did not affect AP-1 activation. Sevoflurane-mediated suppression of AP-1 could be observed in primary CD3 lymphocytes from healthy volunteers, was time-dependent and concentration-dependent, and occurred at concentrations that are clinically achieved. It resulted in an inhibition of AP-1-driven reporter gene activity and of the expression of the AP-1 target gene interleukin-3. Suppression of AP-1 was associated with altered phosphorylation of p38 mitogen-activated protein kinases.


CONCLUSIONS
The data demonstrate that sevoflurane is a specific inhibitor of AP-1 and may thus provide a molecular mechanism for the antiinflammatory effects associated with sevoflurane administration.
Department of Anesthesiology, University Hospital, Freiburg, Germany. torsten@ana1.ukl.uni-freiburg.de
Torsten
T
Loop
Patrick
P
Scheiermann
David
D
Doviakue
Frank
F
Musshoff
Matjaz
M
Humar
Martin
M
Roesslein
Alexander
A
Hoetzel
Rene
R
Schmidt
Burkhard
B
Madea
Klaus K
KK
Geiger
Heike L
HL
Pahl
Benedikt H J
BH
Pannen
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D015153:Blotting, Western; D017252:CD3 Complex / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D000077335:Desflurane; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007202:Indicators and Reagents; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000494:pharmacology; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics; D008738:Methyl Ethers / Q000494:pharmacology*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D018685:Anesthetics, Inhalation; D017252:CD3 Complex; D016207:Cytokines; D007202:Indicators and Reagents; D008738:Methyl Ethers; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D000077149:Sevoflurane; D000077335:Desflurane; D007530:Isoflurane; D008156:Luciferases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate