Dobutamine inhibits phorbol-myristate-acetate-induced activation of nuclear factor-kappaB in human T lymphocytes in vitro.
Adrenergic drugs are often used for hemodynamic support of cardiac output and vasomotor tone in critically ill patients. Recent evidence shows that the administration of these vasoactive drugs may affect cytokine release and could influence the inflammatory response. However, the mechanism of this immunomodulatory effect remains unknown. The nuclear transcription factor-kappaB (NF-kappaB) regulates the expression of many cytokines and plays a central role in the immune response. Therefore, we examined the effects of various adrenergic drugs (dobutamine, xamoterol, clenbuterol, epinephrine, norepinephrine, and phenylephrine) on the activation of NF-kappaB, on the NF-kappaB-driven reporter gene activity, and on the expression of the NF-kappaB target gene interleukin (IL)-8. In addition, we quantified the amount of the NF-kappaB inhibitors IkappaBalpha and IL-10. Here we report that dobutamine inhibited the activation of NF-kappaB in primary human CD3(+) T lymphocytes. Suppression of NF-kappaB involved the stabilization of its inhibitor, IkappaBalpha. The effect appears to be beta(2)-receptor specific, because beta(1)-adrenergic and alpha-adrenergic substances (i.e., xamoterol, epinephrine, norepinephrine, and phenylephrine) did not affect NF-kappaB activation and because dobutamine-mediated inhibition of NF-kappaB could be prevented by a specific beta(2)-antagonist. Our results demonstrate that dobutamine is a potent and specific inhibitor of NF-kappaB, and they thus provide a possible molecular mechanism for the immunomodulation associated with beta-adrenergic therapy.
Loop
Torsten
T
Department of Anesthesiology and Critical Care Medicine, University Hospital, Freiburg, Germany.
Bross
Tobias
T
Humar
Matjaz
M
Hoetzel
Alexander
A
Schmidt
Rene
R
Pahl
Heike L
HL
Geiger
Klaus K
KK
Pannen
Benedikt H J
BHJ
D018663:Adrenergic Agents / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents; D017252:CD3 Complex / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002976:Clenbuterol / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D017307:Xamoterol / Q000494:pharmacology
D018663:Adrenergic Agents; D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D017252:CD3 Complex; D016328:NF-kappa B; D011942:Receptors, Adrenergic, alpha; D004280:Dobutamine; D017307:Xamoterol; D004247:DNA; D013755:Tetradecanoylphorbol Acetate; D002976:Clenbuterol