Dobutamine Inhibits Phorbol-Myristate-Acetate-Induced Activation of Nuclear Factor-??B in Human T Lymphocytes In Vitro

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Abstract
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-κB (NF-κB) 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-κB, on the NF-κB-driven reporter gene activity, and on the expression of the NF-κB target gene interleukin (IL)-8. In addition, we quantified the amount of the NF-κB inhibitors IκBα and IL-10. Here we report that dobutamine inhibited the activation of NF-κB in primary human CD3+ T lymphocytes. Suppression of NF-κB involved the stabilization of its inhibitor, IκBα. The effect appears to be β2-receptor specific, because β1-adrenergic and α-adrenergic substances (i.e., xamoterol, epinephrine, norepinephrine, and phenylephrine) did not affect NF-κB activation and because dobutamine-mediated inhibition of NF-κB could be prevented by a specific β2-antagonist. Our results demonstrate that dobutamine is a potent and specific inhibitor of NF-κB, and they thus provide a possible molecular mechanism for the immunomodulation associated with β-adrenergic therapy.