title: Propranolol Attenuates Surgical Stress-Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy.
abstract: Surgical stress and inflammatory response induce the release of catecholamines and PGs, which may be key factors in facilitating cancer recurrence through immunosuppression. Animal studies have suggested the efficacy of perioperative blockades of catecholamines and PGs in reducing immunosuppression. In this study, to our knowledge, we present the first report of the effects of perioperative propranolol and/or parecoxib on peripheral regulatory T cells (Tregs) in breast cancer patients. Patients were randomly assigned to control, propranolol, parecoxib, and propranolol plus parecoxib groups. We demonstrated that levels of circulating epinephrine, norepinephrine, and PGE2increased in response to surgery. Meanwhile, peripheral FOXP3 mRNA level and Treg frequencies were elevated on postoperative day 7. Propranolol administration, rather than parecoxib, attenuated such elevation of Tregs, indicating the critical roles for catecholamines in surgery-induced promotion of Tregs. Besides, propranolol plus parecoxib treatment demonstrated no additive or synergistic effects. Furthermore, a study of Treg activity on CD4(+)T cell responses to specific tumor Ags was performed in the control and propranolol groups. Propranolol abrogated the increased Treg activity and accompanying suppression of CD4(+)T cell responses after surgery. Finally, we conducted ex vivo experiments on the effects of varying concentrations of epinephrine and/or propranolol on Treg proliferation over PBMCs from breast cancer patients, to provide further direct evidence strengthening our clinical observations. Epinephrine markedly promoted Treg proliferation, whereas propranolol prevented such enhancement effect. In conclusion, our study highlights beneficial roles for propranolol in inhibiting Treg responses in vivo and in vitro, and demonstrates that propranolol could alleviate surgical stress-induced elevation of Tregs in breast cancer patients.
authors.affiliation: Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China;
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China;
authors.forename: Yunli
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China;
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China;
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, Second Xiangya Hospital of Central South University, Changsha 410008, Hunan, China;
authors.forename: Huiying
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Breast Surgery, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China; ouyangwen15@sina.com tongjianbin15@sina.com wuyuhui56@sina.com.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China; Medical Central Laboratory, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China; ouyangwen15@sina.com tongjianbin15@sina.com wuyuhui56@sina.com.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Tong
authors.affiliation: Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China; Seniors Anesthesia and Perioperative Management Research Center, Central South University, Changsha 410013, Hunan, China; and State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410013, Hunan, China ouyangwen15@sina.com tongjianbin15@sina.com wuyuhui56@sina.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Ouyang
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000601:surgery; D002395:Catecholamines / Q000097:blood / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism; D004837:Epinephrine / Q000097:blood; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007555:Isoxazoles / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D018655:Lymphocyte Count; D015409:Mastectomy, Radical; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D011433:Propranolol / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000097:blood; D013312:Stress, Physiological / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007555:Isoxazoles; D012333:RNA, Messenger; D007371:Interferon-gamma; C409945:parecoxib; D011433:Propranolol; D015232:Dinoprostone; D009638:Norepinephrine; D004837:Epinephrine