Norepinephrine (NE) can regulate natural killer (NK) cell activity, but the mechanism remains unclear. In the present study the roles of adrenergic receptors (ARs) in inhibiting NK92-MI cells-mediated cytotoxicity by NE were investigated. To examine the effect of NE on NK92-MI cytotoxicity, a lactate dehydrogenase-release cytotoxicity assay was used to determine the cytotoxicity of NK92-MI cells against K562 cells. To evaluate the possible function of the α, β1 and β2 AR in mediating NE-induced

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... effects, NK92-MI cells were pre-incubated with phenol-amine, CGP20712A and ICI118551 prior to stimulation by NE. To evaluate the role of cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway in the inhibitory effect on cytotoxicity of NK92-MI cell by NE, NK92-MI cells were pre-incubated with PKA inhibitor Rp-8-Br-cAMP prior to stimulation by NE. It was demonstrated that NE decreased cytotoxicity and downregulated the expression of perforin, granzyme B and interferon (IFN)-γ of NK92-MI cells in a dose-dependent manner. Blocking NE functional receptors by ARs antagonists, particularly of β2 AR antagonist, suppressed the inhibitory effect of NE on cytotoxicity and expression of perforin, granzyme B, IFN-γ of NK92-MI cells significantly. Blockade of β2 AR in NE treated NK92-MI cells resulted in a reduction of the expression of phosphorylated (p)-cAMP-responsive element-binding protein (CREB) and intracellular cAMP concentration. Inhibiting the activity of PKA by Rp-8-Br-cAMP in NE treated NK92-MI cells resulted in increased cytotoxicity. The results of the present study suggest that NE can inhibit cytotoxicity and expression of perforin, granzyme B, IFN-γ of NK92-MI cell mainly via the β2-AR/cAMP/PKA/p-CREB signaling pathway.