In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats.
The sympathetic nervous system has been implicated in mediating stress-induced alterations in NK cell activity, particularly through stimulation of beta-adrenergic receptors. However, because catecholamines induce time-dependent alterations in the distribution of NK cells, the impact of beta-adrenergic stimulation on individual NK cell cytotoxicity is not clear, nor are its implications regarding host resistance to metastatic spread. To address these issues, we used the beta-adrenergic agonist, metaproterenol (MP), in F344 rats. The number of blood NK cells doubled within 10 min of MP administration and returned to baseline levels within 1 h. By this time, MP suppressed blood NK activity in a dose-dependent manner. Two beta-adrenergic antagonists, propranolol, which crosses the blood-brain barrier, and nadolol, which does not, blocked this suppression. Corresponding findings were obtained using an NK-sensitive tumor model, the MADB106. MP caused an up to 10 times increase in the number of tumor cells retained in the lungs 1 day after inoculation and a similar rise in the number of consequent lung metastases detected 3 wk later. These effects were dose dependent and nadolol reversible. NK cells appear to play a central role in mediating the tumor-enhancing effects of MP because their selective depletion nearly abolished this effect. Overall, our findings suggest that independent of the transitory increase in numbers of blood NK cells, in vivo beta-adrenergic stimulation suppresses NK activity in the rat. This suppression is induced peripherally and can compromise host resistance to NK-sensitive tumors. Homologies to studies in humans and clinical relevance are discussed.
Shakhar
G
G
Department of Psychology, Tel Aviv University, Israel. shakhar@post.tau.ac.il
Ben-Eliyahu
S
S
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D007113:Immunity, Innate; D007279:Injections, Subcutaneous; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D007958:Leukocyte Count; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008325:Mammary Neoplasms, Experimental; D009921:Metaproterenol / Q000008:administration & dosage; D009248:Nadolol / Q000008:administration & dosage; D011433:Propranolol / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D009248:Nadolol; D009921:Metaproterenol; D011433:Propranolol