A mechanism converting psychosocial stress into mononuclear cell activation was investigated. Psychosocial stress activates the transcription factor NF-κB, which plays a key role in converting stress into cellular activation. In a study, volunteers underwent a laboratory stress test, and NF-κB activity was measured in peripheral blood mononuclear cells (PBMC). In 17 out of 19 volunteers, NF-κB was rapidly induced during stress, alongside increased levels of catecholamines and cortisol, returning to baseline within 60 minutes. Mice transgenic for an NF-κB-controlled β-globin transgene were stressed by immobilization, resulting in increased β-globin expression, which was reduced by the α1-adrenergic inhibitor prazosin. THP-1 cells were induced with physiological amounts of catecholamines, and only noradrenaline resulted in a dose- and time-dependent induction of NF-κB and NF-κB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by α1- and β-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-κB in vitro and in vivo. Activation of NF-κB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response. The cardiovascular system is a target of psychosocial stress, associated with exercise-induced myocardial ischemia, increases in blood pressure, heart rate, and arrhythmias, development of arteriosclerosis, and death. Potential toxic elements in the personality construct such as hostility, anger, cynicism, mistrust, and unhealthy lifestyle increase the risk for cardiovascular disease, suggesting a strong causal relationship between chronic stress and the development of atherosclerosis. Intervention studies in cynomolgus monkeys support this concept, showing not only activation of these processes by mental stress but also reduction of vascular dysfunction and disease by reducing psychosocial stress through β-adrenergic blockade. Consistently, behavioral interventions, stress reduction, and stress management demonstrated benefits over and above usual medical care in hypertensive African Americans and in cardiac patients with evidence of myocardial ischemia. Recent data have indicated an interplay among hypothalamus, pituitary gland, adrenal medulla, and sympathetic nerve terminals as the neuroendocrine response to stress. Further downstream signals converting psychosocial stress into cellular dysfunction and finally into vascular disease are still largely unknown. One observation pointing to a potential mechanism is the induction of inflammatory reactions and the simultaneous decrease of anti-inflammatory reactions leading to enhanced cytokine release and monocytic cell activation. These changes in mononuclear properties are consistent with the activationA mechanism converting psychosocial stress into mononuclear cell activation was investigated. Psychosocial stress activates the transcription factor NF-κB, which plays a key role in converting stress into cellular activation. In a study, volunteers underwent a laboratory stress test, and NF-κB activity was measured in peripheral blood mononuclear cells (PBMC). In 17 out of 19 volunteers, NF-κB was rapidly induced during stress, alongside increased levels of catecholamines and cortisol, returning to baseline within 60 minutes. Mice transgenic for an NF-κB-controlled β-globin transgene were stressed by immobilization, resulting in increased β-globin expression, which was reduced by the α1-adrenergic inhibitor prazosin. THP-1 cells were induced with physiological amounts of catecholamines, and only noradrenaline resulted in a dose- and time-dependent induction of NF-κB and NF-κB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by α1- and β-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-κB in vitro and in vivo. Activation of NF-κB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response. The cardiovascular system is a target of psychosocial stress, associated with exercise-induced myocardial ischemia, increases in blood pressure, heart rate, and arrhythmias, development of arteriosclerosis, and death. Potential toxic elements in the personality construct such as hostility, anger, cynicism, mistrust, and unhealthy lifestyle increase the risk for cardiovascular disease, suggesting a strong causal relationship between chronic stress and the development of atherosclerosis. Intervention studies in cynomolgus monkeys support this concept, showing not only activation of these processes by mental stress but also reduction of vascular dysfunction and disease by reducing psychosocial stress through β-adrenergic blockade. Consistently, behavioral interventions, stress reduction, and stress management demonstrated benefits over and above usual medical care in hypertensive African Americans and in cardiac patients with evidence of myocardial ischemia. Recent data have indicated an interplay among hypothalamus, pituitary gland, adrenal medulla, and sympathetic nerve terminals as the neuroendocrine response to stress. Further downstream signals converting psychosocial stress into cellular dysfunction and finally into vascular disease are still largely unknown. One observation pointing to a potential mechanism is the induction of inflammatory reactions and the simultaneous decrease of anti-inflammatory reactions leading to enhanced cytokine release and monocytic cell activation. These changes in mononuclear properties are consistent with the activation