title: Impaired norepinephrine regulation of monocyte inflammatory cytokine balance in heart failure.
abstract: OBJECTIVE
  To evaluate the effect of norepinephrine on inflammatory cytokine expression inex vivohuman 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) 10-6mol/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/mLvs2.5 ± 2.6 pg/mL,P =0.004). Norepinephrine's effect on TNFα production was reduced in HF (-41% ± 17% HFvs-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% HFvs38% ± 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.
  
  
  CONCLUSIONS
  NE regulation of monocyte inflammatory cytokine production may be reduced in moderate-severe HF, and may be mediated through β-adrenergic receptors.
authors.affiliation: Tien MH Ng, Myron L Toews, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Tien Mh
authors.initials: TM
authors.lastname: Ng
authors.affiliation: Tien MH Ng, Myron L Toews, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
keywords: Cytokines; Heart failure; Inflammation; Monocytes