Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Oct 26, 2016; 8(10): 584-589
Published online Oct 26, 2016. doi: 10.4330/wjc.v8.i10.584
Impaired norepinephrine regulation of monocyte inflammatory cytokine balance in heart failure
Tien MH Ng, Myron L Toews
Tien MH Ng, Myron L Toews, University of Nebraska Medical Center, Omaha, NE 68198, United States
Tien MH Ng, University of Southern California, Los Angeles, CA 90089-9121, United States
Author contributions: Ng TMH was involved in the design, conduct of the study, statistical analysis, and authorship of the manuscript; Toews ML was involved in the design and assays related to the study.
Supported by the American College of Clinical Pharmacy Research Institute.
Institutional review board statement: Study was approved by the University of Nebraska Medical Center Institutional Review Board.
Informed consent statement: The protocol was approved by the Institutional Review Board of the university. All human subjects gave signed informed consent for their participation.
Conflict-of-interest statement: The authors report no conflicts of interest related to the study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Tien MH Ng, Pharm.D., FHFSA, FCCP, BCPS AQ Cardiology, Associate Professor of Clinical Pharmacy and Medicine, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90089-9121, United States. tienng@usc.edu
Telephone: +1-323-4421840 Fax: +1-323-4421681
Received: March 10, 2016
Peer-review started: March 15, 2016
First decision: April 20, 2016
Revised: July 27, 2016
Accepted: August 17, 2016
Article in press: August 18, 2016
Published online: October 26, 2016
Processing time: 230 Days and 9.1 Hours
Abstract
AIM

To evaluate the effect of norepinephrine on inflammatory cytokine expression in ex vivo human monocytes and monocytic THP-1 cells.

METHODS

For human monocyte studies, cells were isolated from 12 chronic heart failure (HF) (66 ± 12 years, New York Heart Association functional class III-IV, left ventricular ejection fraction 22% ± 9%) and 14 healthy subjects (66 ± 12 years). Monocytes (1 × 106/mL) were incubated with lipopolysaccharide (LPS) 100 ng/mL, LPS + norepinephrine (NE) 10-6 mol/L or neither (control) for 4 h. Tumor necrosis factor-alpha (TNFα) and interleukin-10 (IL-10) production were determined by ELISA. Relative contribution of α- and β-adrenergic receptor subtypes on immunomodulatory activity of NE was assessed in LPS-stimulated THP-1 cells incubated with NE, the α-selective agonist phenylephrine (PE), and the β-selective agonist isoproterenol (IPN). NE-pretreated THP-1 cells were also co-incubated with the β-selective antagonist propranolol (PROP), α2-selective antagonist yohimbine (YOH) or the α1-selective antagonist prazosin (PRAZ).

RESULTS

Basal TNFα concentrations were higher in HF vs healthy subjects (6.3 ± 3.3 pg/mL vs 2.5 ± 2.6 pg/mL, P = 0.004). Norepinephrine’s effect on TNFα production was reduced in HF (-41% ± 17% HF vs -57% ± 9% healthy, P = 0.01), and proportionately with NYHA FC. Increases in IL-10 production by NE was also attenuated in HF (16% ± 18% HF vs 38% ± 23% healthy, P = 0.012). In THP-1 cells, NE and IPN, but not PE, induced a dose-dependent suppression of TNFα. Co-incubation with NE and antagonists revealed a dose-dependent inhibition of the NE suppression of TNFα by PROP, but not by YOH or PRAZ. Dose-dependent increases in IL-10 production were seen with NE and IPN, but not with PE. This effect was also antagonized by PROP but not by YOH or PRAZ. Pretreatment of cells with IPN attenuated the effects of NE and IPN, but did not induce a response to PE.

CONCLUSION

NE regulation of monocyte inflammatory cytokine production may be reduced in moderate-severe HF, and may be mediated through β-adrenergic receptors.

Keywords: Monocytes; Cytokines; Heart failure; Inflammation

Core tip: In evaluating the relationship between sympathetic activation and inflammatory cytokine production in heart failure, we demonstrated that norepinephrine (NE) has reduced ability to suppress the production of the proinflammatory cytokine tumor necrosis factor-alpha, and increase anti-inflammatory interleukin-10, in human isolated monocytes from heart failure compared to healthy subjects. It appears to be mediated through beta-adrenergic, and not alpha-adrenergic, receptors based on monocytic THP-1 cells dose-response experiments. This suggests that the diminished immunomodulatory activity of NE in heart failure is primarily due to altered beta-adrenergic receptor function, and may represent an immunologic mechanism for the positive effects of beta-adrenergic blocking agents.