Published online Oct 26, 2016. doi: 10.4330/wjc.v8.i10.584
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
To evaluate the effect of norepinephrine on inflammatory cytokine expression in ex vivo human monocytes and monocytic THP-1 cells.
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).
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.
NE regulation of monocyte inflammatory cytokine production may be reduced in moderate-severe HF, and may be mediated through β-adrenergic receptors.
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.