Suppression of NK Cell Activity and of Resistance to Metastasis by Stress: A Role for Adrenal Catecholamines and Beta-Adrenoceptors

Neuroimmunomodulation. 2000;8(3):154-64. doi: 10.1159/000054276.


Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and beta(1)- and beta(2)-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective beta-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective beta(1)- (atenolol, 1-6 mg/kg) and a selective beta(2)-antagonist (either butoxamine 4-32 mg/kg or ICI-118,551 0.3-8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1-1 mg/kg) or of a beta-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating beta(1)- and beta(2)-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenal Medulla / immunology
  • Adrenal Medulla / physiology*
  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Antagonists
  • Animals
  • Catecholamines / physiology*
  • Disease Models, Animal
  • Epinephrine / metabolism
  • Female
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Male
  • Mammary Neoplasms, Experimental / immunology*
  • Mammary Neoplasms, Experimental / metabolism
  • Metaproterenol / metabolism
  • Rats
  • Rats, Inbred F344
  • Receptors, Adrenergic, beta-1 / physiology*
  • Receptors, Adrenergic, beta-2 / physiology*
  • Stress, Physiological / immunology*
  • Stress, Physiological / metabolism
  • Swimming
  • Sympathetic Nervous System / metabolism
  • Sympathomimetics / metabolism
  • Tumor Cells, Cultured / transplantation


  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Antagonists
  • Catecholamines
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Sympathomimetics
  • Metaproterenol
  • Epinephrine