Do Stress Responses Promote Leukemia Progression? An Animal Study Suggesting a Role for Epinephrine and Prostaglandin-E2 through Reduced NK Activity

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition

Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids

IL-12 is a prominent Th1 differentiator and leukocyte activator. Ample studies showed suppression of IL-12 production by numerous stress factors, including prostaglandins, catecholamines, glucocorticoids, and opioids, but did so in vitro and in the context of artificial leukocyte activation, not simulating the in vivo setting. In a recent study we reported in vivo suppression of plasma IL-12 levels by behavioral stress and surgery. The current study aims to elucidate neuroendocrine mechanisms underlying this phenomenon in naïve F344 rats. To this end, both adrenalectomy and administration of specific antagonists were used, targeting the aforementioned stress factors. The results indicated that corticosterone and prostaglandins are prominent mediators of the IL-12-suppressing effects of stress and surgery, apparently through directly suppressing leukocyte IL-12 production. Following surgery, endogenous prostaglandins exerted their effects mainly through elevating corticosterone levels. Importantly, stress-induced release of epinephrine or opioids had no impact on plasma IL-12 levels, while pharmacological administration of epinephrine reduced plasma IL-12 levels by elevating corticosterone levels. Last, a whole blood in vitro study indicated that prostaglandins and corticosterone, but not epinephrine, suppressed IL-12 production in non-stimulated leukocytes, and only corticosterone did so in the context of CpG-C-induced IL-12 production. Overall, the findings reiterate the notion that results from in vitro or pharmacological in vivo studies cannot indicate the effects of endogenously released stress hormones under stress/surgery conditions. Herein, corticosterone and prostaglandins, but not catecholamines or opioids, were key mediators of the suppressive effect of stress and surgery on in vivo plasma IL-12 levels in otherwise naïve animals

Metastatic promoting effects of LPS: Sexual dimorphism and mediation by catecholamines and prostaglandins

Inflammation is implicated in several medical conditions that are sexually dimorphic, including depression, cardiovascular diseases, autoimmunity, and presumably cancer progression. Here we studied the effects of the proinflammatory agent, LPS, on MADB106 lung tumor retention (LTR), and sought to elucidate underlying mechanisms and sexual dimorphism. F344 male and female rats were administered with LPS (0.001-1 mg/kg i.v.) simultaneously with tumor cell inoculation, and treated with a b-blocker (nadolol, 0.2-0.3 mg/kg s.c.), a COX inhibitor (indomethacin, 4 mg/kg s.c.) or both drugs. To study the role of NK cells, numbers and cytotoxicity of marginating-pulmonary NK cells were studied, and selective in vivo NK-depletion was employed. Serum levels of corticosterone, IL- 6, and TNF-a were also assessed. The findings indicated that LPS increased LTR in both sexes, but 10-fold higher doses were needed in females to reach the increase evident in males. Additionally, nadolol and indomethacin reduced the effects of LPS, more so in males. In vivo NK-depletion and ex vivo NK activity studies suggested that LPS affected LTR through both NK-independent and NKdependent mechanisms, the latter mediated through prostaglandin release in males. Corticosterone, IL-6, and TNF-a responses to LPS were sexually dimorphic, but were not associated with LPS or drugs' impacts on LTR. Overall, our findings demonstrate sexual dimorphism in LPS-induced elevated susceptibility to MADB106 experimental metastasis, and in potential humoral underlying mechanisms. Further studies are needed to elucidate additional immunological and non-immunological mediators of these dimorphisms, as well as to assess their involvement in other sexually dimorphic pathologies that are associated with inflammation

Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids

IL-12 is a prominent Th1 differentiator and leukocyte activator. Ample studies showed suppression of IL-12 production by numerous stress factors, including prostaglandins, catecholamines, glucocorticoids, and opioids, but did so in vitro and in the context of artificial leukocyte activation, not simulating the in vivo setting. In a recent study we reported in vivo suppression of plasma IL-12 levels by behavioral stress and surgery. The current study aims to elucidate neuroendocrine mechanisms underlying this phenomenon in naïve F344 rats. To this end, both adrenalectomy and administration of specific antagonists were used, targeting the aforementioned stress factors. The results indicated that corticosterone and prostaglandins are prominent mediators of the IL-12-suppressing effects of stress and surgery, apparently through directly suppressing leukocyte IL-12 production. Following surgery, endogenous prostaglandins exerted their effects mainly through elevating corticosterone levels. Importantly, stress-induced release of epinephrine or opioids had no impact on plasma IL-12 levels, while pharmacological administration of epinephrine reduced plasma IL-12 levels by elevating corticosterone levels. Last, a whole blood in vitro study indicated that prostaglandins and corticosterone, but not epinephrine, suppressed IL-12 production in non-stimulated leukocytes, and only corticosterone did so in the context of CpG-C-induced IL-12 production. Overall, the findings reiterate the notion that results from in vitro or pharmacological in vivo studies cannot indicate the effects of endogenously released stress hormones under stress/surgery conditions. Herein, corticosterone and prostaglandins, but not catecholamines or opioids, were key mediators of the suppressive effect of stress and surgery on in vivo plasma IL-12 levels in otherwise naïve animals. © 2014 Elsevier Ltd