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Anesth Analg 2003;97:205-209
© 2003 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

Dobutamine Inhibits Monocyte Chemoattractant Protein-1 Production and Chemotaxis in Human Monocytes

Chi-Yuan Li, MD MS*, Chien-Sung Tsai, MD{dagger}, Sheau-Huei Chueh, PhD{ddagger}, Ping-Ching Hsu, MS{dagger}, Jia-Yi Wang, PhD§, Chih-Shung Wong, MD PhD*, and Shung-Tai Ho, MD MS*

Departments of *Anesthesiology and {dagger}Surgery, Tri-Service General Hospital; and Departments of {ddagger}Biochemistry and §Physiology, National Defense Medical Center, Taipei, Taiwan, Republic of China

Address correspondence and reprint requests to Chi-Yuan Li, MD, MS, Department of Anesthesiology, #325 Section 2, Cheng-Kung Rd., Taipei, Taiwan, ROC. Address e-mail to cyli{at}ndmctsgh.edu.tw


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
It has been reported that, in patients with acute myocardial infarction or congestive heart failure, monocyte chemoattractant protein-1 (MCP-1) plays an important role in the development of inflammatory responses and that the level of MCP-1 is correlated with the severity of the disease. We conducted this study to investigate the effects of dobutamine and dopamine on lipopolysaccharide (LPS)-induced MCP-1 production in human monocytic THP-1 cells. Monocytes were incubated in vitro with LPS for 16 h at 37°C in the presence or absence of dobutamine or dopamine. Enzyme-linked immunosorbent assay was used to examine the effect of dobutamine on MCP-1 synthesis, with the MCP-1 messenger RNA expression examined by reverse transcriptase-polymerase chain reaction. Dobutamine inhibited LPS-induced production of MCP-1, as well as messenger RNA expression, in a dose-dependent manner, whereas dopamine had no significant effect. Furthermore, we demonstrated that dobutamine suppressed MCP-1-induced chemotaxis and peak [Ca2+]i in monocytic THP-1 cells. These findings suggest that dobutamine may modulate monocyte activation, such as chemotaxis and [Ca2+]i, as well as MCP-1 production, during therapy for congestive heart failure.

IMPLICATIONS: Monocyte chemoattractant protein-1 (MCP-1) plays important roles in the inflammatory processes associated with pathogenesis of cardiovascular diseases. In this study, dobutamine was found to inhibit lipopolysaccharide-induced MCP-1 production and messenger RNA expression, as well as MCP-1-induced chemotaxis and peak [Ca2+]i, in human monocytes.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The attraction of leukocytes to tissues is essential for infection, inflammation, and immune response. This process is controlled by chemokines, which are important in the control of leukocyte activation and traffic in several immune-mediated and inflammatory disorders, such as bronchial asthma, rheumatoid arthritis, inflammatory bowel disease, and acute respiratory distress syndrome (1–5). There are four families of chemokines according to their sequence homology and the position of the first two cysteine residues, of which there are two main subfamilies: CXC chemokines and CC chemokines (6). In general, CXC chemokines act predominantly on neutrophils, whereas CC chemokines stimulate monocytes, eosinophils, basophils, and lymphocytes.

Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family. It is characterized by chemoattractant activity for monocytes, T cells, mast cells, and basophils (6,7). In addition to promoting the transmigration of circulating monocytes into the tissues, MCP-1 exerts various other effects on monocytes, including superoxide anion induction, chemotaxis, and calcium flux (7). Growing evidence suggests that MCP-1 is important in the immunological and inflammatory processes associated with the pathogenesis and progression of cardiovascular diseases, such as atherosclerosis (8–10), acute coronary syndrome (11), and congestive heart failure (CHF) (12). An increase of the circulating levels of MCP-1 has been observed in cases of acute myocardial infarction or CHF (13,14). Moreover, increased expression of MCP-1 has been demonstrated in the failing myocardium during myocarditis (15).

The sympathomimetic amines, especially dobutamine and dopamine, have been widely used in the treatment of patients with symptomatic CHF caused by systolic dysfunction. Dobutamine acts mainly as a selective ß1 agonist, exerting a potent inotropic effect with concurrent afterload reduction. Dopamine activates the DA1 receptors, which increases cerebral, coronary, and renal blood flow and, in combination with its positive inotropic effect, provides hemodynamic benefits (16). A reputation for CHF treatment has been established for these two drugs over decades of clinical use.

Increased MCP-1 is observed in patients with CHF, and it is critically implicated in the pathogenesis and progression of the disease. Dobutamine and dopamine are the therapeutic mainstay for CHF treatment. This study examines the effects of dobutamine and dopamine on MCP-1 production, because there have been no studies investigating such relationships. In addition, the hypothesis that dobutamine exerts its effect on MCP-1-induced activation of THP-1 monocytic cells, as reflected in chemotaxis and peak intracellular calcium concentration ([Ca2+]i), was also tested.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The human monocytic cell line THP-1 (American Type Culture Collection, Rockville, MD) was cultured in RPMI 1640 medium (Sigma Chemical Co., St. Louis, MO) supplemented with 10% fetal bovine serum, 100 U/mL of penicillin, and 100 µg/mL of streptomycin at 37°C and 5% CO2 in a humidified incubator. Cells were centrifuged and resuspended in fresh media in 24-well plates at a concentration of 106/mL for 24 h before experimental use.

After 16-h treatments with lipopolysaccharide (LPS) (serotype O111:B4; Sigma Chemical Co.) and/or 0.1–100 µM of drugs (dobutamine, dopamine, and salbutamol; Sigma Chemical Co.), supernatants were stored at -70°C until assay. Determination of MCP-1 concentration was performed according to the manufacturer’s recommendations (R & D Systems, Minneapolis, MN) with some modification. Each well of a high-binding-efficiency 96-well enzyme-linked immunosorbent assay plate was coated with mouse anti-human MCP-1 monoclonal antibody (100 µL at 1 µg/mL) in phosphate-buffered saline (PBS) at room temperature overnight. The plate was then washed three times with PBS containing 0.05% Tween 20 (PBS-T). Residual binding sites were blocked with 1% bovine serum albumin and 5% sucrose (300 µL per well; Sigma Chemical Co.) in PBS with 0.05% NaN3 and incubated for 1 h at room temperature. After washing with PBS, standard MCP-1 solution or cell supernatants (100 µL per well) were added in duplicate to the coated wells, incubated for 2 h at room temperature, and washed 3 times with PBS-T. The plates were then incubated with biotinylated goat anti-human MCP-1 detection antibodies (100 µL at 0.1 µg/mL) for 2 h at room temperature. After the wash, 100 µL of streptavidin horseradish peroxidase (1:2500 dilution of 1.25 mg/mL solution) was added and incubated for 20 min at room temperature. After a triple wash, 100 µL of substrate solution containing a 1:1 mixture of H2O2 and tetramethylbenzidine was added and incubated for another 20 min at room temperature. The reaction was stopped by adding 50 µL of stop solution (1 M H2SO4), and the MCP-1 concentrations were measured with a microplate reader (Dynatech, Guernsey, UK).

The THP-1 cells were incubated at 37°C for 4 h with 0.1 µg/mL of LPS in the presence or absence of dobutamine, dopamine, and salbutamol. Total RNA was extracted from cell pellets (1 x 106 cells) by using the single-step phenol and guanidine isothiocyanate method (TRIzol; Gibco BRL, Grand Island, NY). The RNA was washed twice in ethanol and precipitated, and the amount of total RNA was quantified by spectrophotometry at 260 nm (Uvikon 940 spectrophotometer; Kontron, Zurich, Switzerland). Total RNA (5 ng per sample) was reverse-transcribed by using SuperScript II RNase H reverse transcriptase (Gibco BRL) and primed with oligo dT according to the manufacturer’s instructions. The reaction mixture was incubated at 42°C for 50 min for the reverse-transcription reaction.

In brief, polymerase chain reaction (PCR) was performed with 25 pmol of each primer in a total volume of 25 µL. The reaction buffer consisted of 50 mmol/L of Tris-HCl, 0.02 mol/L of (NH4)2SO4, 1.5 mmol/L of MgCl2, 0.2 mmol/L of deoxy nucleoside triphosphate, and 0.05 U/µL of DNA polymerase. A minimum of 3 different complementary DNA concentrations served as the template for amplification through 19–31 cycles of denaturation (60 s at 94°C), primer annealing (60 s at 58°C), and DNA extension (90 s at 72°C) in a GeneAmp PCR System 2400 (PerkinElmer, Norwalk, CT). All amplifications were performed by using a single set of gene-specific sense and antisense oligonucleotide primers designed to flank at least one intron. Amplification of messenger RNA (mRNA) from the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was used to produce an internal quality standard. The primer sequences were as follows: MCP-1 sense, 5'-GCTCATAGCAGCCACCTTCATTC 3'; MCP-1 antisense, 5'-TGCAGATTCTTGGGTTGTGGAG 3'; GAPDH sense, 5'-GGGGAGCCAAAAGGGTCATCATCT 3'; and GAPDH antisense, 5'-GAGGGGCCATCCACAGTCTTCT 3'.

Amplified products were electrophoresed on 1.5% agarose gel stained with ethidium bromide, and a 100-base pair DNA ladder (Gibco BRL) was used as a molecular-weight marker. The sample products were visualized with ultraviolet transillumination, and the gel was photographed. Total RNA from the LPS (0.1 µg/mL)-activated monocytic THP-1 cell line (American Type Culture Collection) was used as a positive control. The experimental condition and number of PCR cycles were predetermined to ensure that the amount of MCP-1 and housekeeping gene (GAPDH) fragments were in the linear range of amplification. GAPDH was used as the standard to control for variations in RNA isolation.

Monocyte chemotaxis was measured by using a 24-well Micro Chemotaxis Transwell® plate (Coring Costar, Cambridge, MA). THP-1 cells were resuspended at 1.5 x 106/mL and transferred to the upper chamber of the Micro Chemotaxis chamber. The chemoattractant, MCP-1 (10 nM in RPMI medium with 1 mg/mL of bovine serum albumin), was added to the lower chamber. The lower and upper chambers were separated by a polycarbonate membrane (5-µm pore size). The THP-1 cells were left to transmigrate for 120 min. After a 2-h incubation at 37°C in a humidified atmosphere with 5% CO2, the number of monocytes that had migrated to the lower compartment was determined by counting the cells by using light microscopy.

Calcium flux assays were performed per the method described previously (17,18). For calcium measurements, recombinant human MCP-1 was obtained by using the R & D Systems. Monocytic THP-1 cells were suspended at a density of 2 x 106/mL in Hanks’ balanced salt solution containing 1.3 mM CaCl2, 10 mM HEPES (pH 7.3), and 1% fetal calf serum (FCS). The cells were loaded with 10 mM Fura-2 AM (Molecular Probes Inc., Eugene, OR) for 1 h at 30°C with occasional shaking. Loaded cells were washed twice with centrifugation and resuspended at a concentration of 106/mL. The temperature of the cell suspension was kept at 37°C, and immediately before each assay, the cells were collected by centrifugation, resuspended in 2 mL of Hanks’ balanced salt solution/HEPES/FCS, and added to a cuvette in a temperature-controlled holder (37°C), with continuous stirring. The [Ca2+]i was measured by testing the relative ratio of the fluorescence emission intensities ({lambda}ex 505 nm) excited both {lambda}em 340 and 380 nm, by using the AR-CM-MIC Cation Measurement System (Spex Industries Inc.).

All data are presented as mean ± SEM. One-way analysis of variance was used for all statistical comparisons, and the Student-Newman-Keuls test was conducted for multiple comparisons. A P value of <0.05 was considered indicative of significant between-group differences. SigmaStat software (Jandel Scientific, Erkrath, Germany) was used for all statistical analysis.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
THP-1 cells were incubated with dobutamine or dopamine to determine whether LPS-induced secretion of MCP-1 was inhibited. After a 16-h incubation, a minimal quantity of MCP-1 was produced by the THP-1 cells in the media (21 ± 1 pg/mL). LPS-induced MCP-1 production (1334 ± 422 pg/mL) was significantly inhibited by dobutamine in a dose-dependent manner (Fig. 1). Salbutamol’s suppressive effect on MCP-1 production was similar to that of dobutamine (Fig. 1). By contrast, no significant effect on LPS-induced MCP-1 production was demonstrated for dopamine at any of the tested concentrations (Fig. 1). To test for dobutamine inhibition of MCP-1 at the transcription level, MCP-1 mRNA content was measured in THP-1 cells incubated with LPS in the presence or absence of dobutamine, dopamine, or salbutamol. Exposure to either dobutamine or salbutamol caused a dose-dependent decrease in MCP-1 mRNA levels, as determined at 4 h after LPS (Fig. 2). Dopamine had no effect on MCP-1 mRNA levels.



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  		Figure 1. Effect of dobutamine, dopamine, and salbutamol on lipopolysaccharide (LPS)-induced monocyte chemoattractant protein-1 (MCP-1) production with human monocytic THP-1 cells at 16 h after LPS (0.1 µg/mL). *P < 0.05; **P < 0.01: significant suppression of MCP-1 in comparison to LPS controls (n = 5 or 6).

 


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  		Figure 2. Dobutamine suppressed monocyte chemoattractant protein-1 (MCP-1) messenger RNA expression. Human monocytic THP-1 cells were stimulated with lipopolysaccharide (LPS; 0.1 µg/mL), with medium alone (control), or with dobutamine, dopamine, and salbutamol (0.1, 1, and 10 µM, respectively). Reverse transcriptase-polymerase chain reaction with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and MCP-1 primers was performed on total RNA extracts 4 h after the initiation of culture.

 
Cell migration was 1.3 ± 0.5 x 106 cells in the absence of MCP-1 (random migration), increasing to 2.9 ± 0.6 x 106 cells after MCP-1 stimulation. The effect of dobutamine on MCP-1-induced monocyte chemotaxis was assessed in therapeutic (0.1–10 µM) and pharmacological (10–100 µM) concentration ranges. As depicted in Figure 3, treatment of human monocytic THP-1 cells with different concentrations of dobutamine significantly reduced the THP-1 cell chemotaxis induced by MCP-1 (10 nM). By contrast, under the same experimental conditions, dopamine did not inhibit this chemotaxis at any concentration tested. Reduction of dobutamine THP-1 cell chemotaxis was concentration dependent, with 90% of maximal inhibition demonstrated at 100 µM in this study.



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  		Figure 3. Effect of dobutamine and dopamine on monocyte chemoattractant protein-1 (MCP-1)-induced THP-1 monocytic cell chemotaxis. THP-1 monocytic cells were incubated with medium alone or with increasing concentrations of dobutamine or dopamine at 37°C for 120 min in the upper compartment of a Micro Chemotaxis chamber. MCP-1 (10 nM) was added in the lower compartment. The number of monocytes that migrated to the lower compartment was determined by counting the cells with light microscopy. The inhibition percentage is expressed as mean ± SEM for four separate experiments performed in duplicate. *P < 0.05; **P < 0.01: indicates significant suppression of MCP-1-induced chemotaxis.

 
The increase in [Ca2+]i represents a key event in chemokine-induced monocyte activation. A rapid, transient, and concentration-dependent increase in [Ca2+]i was observed with MCP-1 treatment (10 nM). Treatment with dobutamine (10–100 µM) reduced MCP-1-induced peak [Ca2+]i in THP-1 cells (Fig. 4).



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  		Figure 4. Effect of dobutamine (DB) on monocyte chemoattractant protein-1 (MCP-1)-induced intracellular calcium concentration ([Ca2+]i) change in human THP-1 monocytic cells. The cells were loaded with fura-2, and MCP-1 (10 nM) was added with or without dobutamine pretreatment. Stimulus-dependent [Ca2+]i change was calculated from real-time fluorescence recording. A rapid, transient, and concentration-dependent increase in [Ca2+]i was observed with MCP-1 treatment (10 nM). Treatment with dobutamine (10–100 µM) reduced the MCP-1-induced peak [Ca2+]i in THP-1 cells.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Increasing evidence suggests that MCP-1 is important in the immunological and inflammatory processes associated with the pathogenesis and progression of cardiovascular diseases, such as atherosclerosis, unstable angina, and CHF (14,15,19). This study is the first to clearly demonstrate that, in vitro, dobutamine causes a dose-dependent inhibition of MCP-1 production in human monocytic THP-1 cells. Moreover, we found that dobutamine inhibited LPS-induced MCP-1 mRNA expression, suggesting that dobutamine inhibits MCP-1 production at a transcriptional level. Dopamine has no effect on either MCP-1 protein production or mRNA expression, however.

Dobutamine is a ß1-adrenergic receptor agonist. To determine whether ß2-specific receptor stimulation can also inhibit MCP-1 production, the effect of salbutamol (a ß2-adrenergic receptor agonist) was compared with that of dobutamine. The suppressive effect on MCP-1 production was similar for the two. The results suggest that activation of either the ß1 or ß2 receptor may independently inhibit the MCP-1 production response to LPS in monocytes. ß-Adrenoreceptor activation increases intracellular 3',5'-cyclic adenosine monophosphate (cAMP) through the activation of adenylate cyclase (20,21), and increased cAMP levels reduced monocyte cytokine production in other studies (22–24). In our study, similar inhibitory effects on MCP-1 production were demonstrated for both dobutamine (ß1) and salbutamol (ß2) (81% ± 3% and 50% ± 22% inhibition at 1 µM, respectively). This may mainly be a consequence of the increased cAMP levels associated with ß-adrenoreceptor stimulation in the human monocytic THP-1 cells. Although analysis of our data does not prove that MCP-1 production is positively regulated by cAMP, the results do suggest, at least in part, that these may be such a mechanism.

Activation of leukocytes and migration from the circulation to areas of myocardial inflammation appear to be important factors in the immunological responses associated with CHF (25). Further, excessive chemokine activation may result in inappropriate inflammation and lead to cell and tissue damage. Additionally, chronic inflammation with leukocyte infiltration has been observed in the failing human myocardium (26). MCP-1 exhibits chemotactic activity for monocytes and lymphocytes, and it has been postulated that this is a crucial event for the accumulation of mononuclear leukocytes in myocarditis (27). In patients with acute myocarditis, large plasma MCP-1 levels are correlated with fatal outcome (27). The MCP-1 that induced chemotaxis was also a potent stimulus for intracellular Ca2+ mobilization in human monocytes. [Ca2+]i increase represents a key event in chemokine-induced monocyte activation. By playing a crucial role in the recruitment and activation of leukocytes, MCP-1 may indirectly lead to damage and dysfunction of the cardiac muscle in CHF patients through activation and production of reactive oxygen species (7,14,28). Previously, Tool et al. (29) demonstrated that ß2-adrenergic agonists and phosphodiesterase inhibitors suppressed the chemotactic response in human eosinophils. In this study, we found that dobutamine suppressed MCP-1-induced chemotaxis and peak [Ca2+]i in monocytic THP-1 cells, indicating that dobutamine may suppress the recruitment and activation of leukocytes. However, further evaluation is needed of dobutamine’s effects on other biological processes of pathogenic importance in heart failure, including fibrosis, angiogenesis, and apoptosis.

Recent evidence of a possible pathogenic role for chemokines in CHF suggests that modulation of the chemokine network may offer novel therapeutic modalities in these disorders. Moreover, Aukrust et al. (14) demonstrated that monocytes isolated from heart disease patients released larger amounts of MCP-1 in comparison to analogs from healthy subjects; this increase possibly contributed to the pathologic conditions. In this study, dobutamine inhibited MCP-1 production, as well as MCP-1-induced chemotaxis and activation in human monocytic cells. These results suggest that dobutamine may be of benefit in the treatment of congestive heart disease. Further in vivo studies are warranted to establish the impact of dobutamine’s effects on MCP-1-mediated monocyte response during inflammation.

In conclusion, we have demonstrated that dobutamine, but not dopamine, inhibits MCP-1 production in human monocytes in vitro and that this regulation occurs, at least in part, at the transcriptional level. Moreover, dobutamine suppresses MCP-1-induced chemotaxis and peak [Ca2+]i in human monocytic cells. Therefore, further understanding of the mechanism(s) by which dobutamine inhibits MCP-1 production, as well as MCP-1-induced activation, may help identify and provide insight into therapies that will limit the progression of congestive heart disease.


   Acknowledgments
 
Supported by grants from the Tri-Service General Hospital (TSGH-C91-78) and the National Science Council (NSC 91-2314-B-016-088), Taiwan, Republic of China.


   References
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 Introduction
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Accepted for publication February 24, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press