title: Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period.
abstract: We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, β-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed - both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and β-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune-stimulation.
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Levi
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Matzner
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Goldfarb
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Sorski
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Shaashua
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Melamed
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Rosenne
authors.affiliation: Johns Hopkins University - ‡School of Nursing, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: G G
authors.initials: GG
authors.lastname: Page
authors.affiliation: Neuroimmunology Research Unit, Sagol School of Neuroscience, and The School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Ben-Eliyahu
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D007694:Killer Cells, Natural; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013315:Stress, Psychological / Q000276:immunology*
chemical_list: D002395:Catecholamines; C527702:CpG ODN 2395; D005938:Glucocorticoids; D007155:Immunologic Factors; D009838:Oligodeoxyribonucleotides; D011448:Prostaglandin Antagonists
keywords: Catecholamines; CpG-C; Glucocorticoids; Immune stimulation; NK; Ongoing stress; Prostaglandins