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CRITICAL CARE AND TRAUMA

Dobutamine Modulates Lipopolysaccharide-Induced Macrophage Inflammatory Protein-1 and Interleukin-8 Production in Human Monocytes

Chi-Yuan Li, MD MS^*, Chien-Sung Tsai, MD, Ping-Ching Hsu, MS, Ching-Tang Wu, MD^*, Chih-Shung Wong, MD PhD^*, and Shung-Tai Ho, MD MS^*

Departments of *Anesthesiology and Surgery, Tri-Service General Hospital, National Defense Medical Center, National Defense University, 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

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Chemokines mediate the migration of leukocytes to sites of inflammation. The CC chemokine macrophage inflammatory protein (MIP)-1 and the CXC chemokine interleukin (IL)-8 are reported to play an important role in early inflammatory stages, wound healing, sepsis, and some cardiovascular diseases, including acute coronary syndromes and congestive heart failure. We conducted this study to investigate the effect of dobutamine on lipopolysaccharide (LPS)-induced MIP-1 and IL-8 production by human monocytic THP-1 cells. Monocytes were incubated in vitro with LPS for 4 or 16 h at 37°C in the presence or absence of dobutamine. The effect of dobutamine on MIP-1 and IL-8 synthesis was examined by using an enzyme-linked immunosorbent assay, and MIP-1 and IL-8 messenger RNA (mRNA) were examined by using reverse transcriptase-polymerase chain reaction. Dobutamine significantly inhibited LPS-induced MIP-1 and IL-8 production by THP-1 cells in a dose-dependent manner. Salbutamol had a similar suppressive effect on LPS-stimulated MIP-1 and IL-8 production. MIP-1 mRNA was also suppressed by 10 µM dobutamine, whereas, at the same concentration, dobutamine had no significant effect on the IL-8 mRNA level. Moreover, we found that dobutamine suppressed the MIP-1-induced chemotaxis in THP-1 differentiated macrophages. These findings suggest that dobutamine may inhibit macrophage chemotaxis, as well as MIP-1 and IL-8 production by monocytes. The site of chemokine regulation is at the transcriptional level for MIP-1 and might be at the posttranscriptional level for IL-8.

IMPLICATIONS: Macrophage inflammatory protein (MIP)-1 and interleukin (IL)-8 are reported to play an important role in early inflammatory stages, wound healing, sepsis, and some cardiovascular diseases. Our study suggests that dobutamine may inhibit macrophage chemotaxis, as well as lipopolysaccharide-induced MIP-1 and IL-8 production by human monocytes.

	Introduction

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Tissue injury associated with bacterial infections results, in part, from infiltrating leukocytes recruited by local mediators to the site of infection. This process is controlled by chemokines, which play important roles in controlling leukocyte activation and regulating leukocyte trafficking in several immune-mediated and inflammatory disorders, such as bronchial asthma, inflammatory bowel disease, rheumatoid arthritis, allograft rejection, and human immunodeficiency virus infection (1–5). There are four families of chemokines; these families are based on the sequence homology and the position of the first two cysteine residues, of which there are two main subfamilies: CXC chemokines and CC chemokines. Typically, CXC chemokines, such as interleukin (IL)-8 and growth-related oncogene-, are chemotactic for neutrophils, whereas CC chemokines, such as the monocytes chemoattractant protein-1 and macrophage inflammatory protein (MIP) -1, are chemotactic for monocytes and lymphocytes (6,7).

MIP-1 activates mast cells and basophils to be chemotactic for T cells and monocytes and to induce an oxidative burst in neutrophils (8,9). The activity of MIP-1 in infection and inflammatory diseases, such as human immunodeficiency virus, rheumatoid arthritis, and osteoarthritis, has been investigated (10,11). IL-8 is a potent neutrophil activator produced in pulmonary disease (12), surgical wounds (13), and central nervous system injuries (14). Both MIP-1 and IL-8 are involved in the early inflammatory stages, wound healing, sepsis, and some cardiovascular diseases (15–18). Moreover, increased plasma levels of IL-8 were found in patients with multiple organ failure and might be an early predictor of survival after blunt accident trauma (16,19).

Prior studies documented that the production of monocyte/macrophage inflammatory mediators is responsive to catecholamine action. The effects of ß-adrenergic drugs (especially ß₂) on the production of cytokines have been extensively investigated (20–22). Dobutamine acts mainly as a selective ß₁ agonist, exerting a potent inotropic effect with concurrent afterload reduction (23). It has been widely used in the treatment of patients with systolic dysfunction of septic shock. Nonetheless, the effect of dobutamine on chemokine production has not been well studied. In this study, the possible effect of dobutamine on lipopolysaccharide (LPS)-induced IL-8 and MIP-1 production by human monocytic THP-1 cells was investigated.

	Methods

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Monocytes from the human monocytic cell line THP-1 (American Type Culture Collection, Rockville, MD) were 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 in 5% CO₂ in a humidified incubator. Cells were centrifuged and resuspended with fresh medium in 24-well plates at a concentration of 10⁶/mL and incubated for 24 h before experimental use.

After 4- or 16-h treatments with LPS (serotype O111:B4; Sigma Chemical Co.), 0.1–100 µM drugs (dobutamine and salbutamol, both obtained from Sigma Chemical Co.), or both, supernatants were stored at -70°C until assay. Chemokine concentrations were determined by enzyme-linked immunosorbent assay, according to the manufacturer’s (R&D Systems, Minneapolis, MN) guidelines, with some modification. Each well of a high-binding-efficiency 96-well enzyme-linked immunosorbent assay plate was coated with mouse anti-human MIP-1 or IL-8 monoclonal antibody (100 µL at 1 µg/mL) in phosphate-buffered saline (PBS) at room temperature overnight. Then the plate was washed three times with PBS containing 0.05% Tween-20. Residual binding sites were blocked with 1% bovine serum albumin 5% sucrose (BSA, 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 MIP-1 or IL-8 solution or cell supernatants (100 µL per well) were added in duplicate to the coated wells, incubated for 2 h at room temperature, and again washed three times with PBS containing 0.05% Tween-20. Then the plates were incubated with biotinylated goat anti-human MIP-1 or IL-8 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 MIP-1 or IL-8 concentration was measured with a microplate reader (Dynatech, Guernsey, UK).

The THP-1 cells were incubated at 37°C for 2 or 4 h with 0.1 µg/mL of LPS in the presence or absence of dobutamine or 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). A total of 5 ng of total RNA per sample was reverse-transcribed by using SuperScript RNase H Reverse Transcriptase (Gibco BRL) and oligo-dT priming, according to the manufacturer’s instructions. The reaction mixture was incubated at 42°C for 50 min to complete 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 deoxynucleoside triphosphate, and 0.05 U/µL of DNA polymerase. A minimum of three different complementary DNA concentrations served as templates for amplification consisting of 19 to 31 cycles of denaturation, primer annealing, and DNA extension in a GeneAmp PCR System 2400 (PerkinElmer, Norwalk, CT). All amplifications were performed with a single set of gene-specific sense and antisense oligonucleotide primers. Primers were designed to flank at least one intron. Amplification of messenger RNA (mRNA) for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the internal quality control standard. The primer sequences were as follows: MIP-1 sense, 5'-CTGCCCTTGCTGTCCTCCTCTG-3'; MIP-1 antisense, 5'-CTGCCGGCTTGGCTTGGTTA-3'; IL-8 sense, 5'-ATGACTTCCAAGCTGGCCGTGGCT-3'; IL-8 antisense, 5'-TCTCAGCCCTCTTCAAAAACTTCTC-3'; GAPDH sense, 5'-GGGGAGCCAAAAGGGTCATCATCT-3'; and GAPDH antisense, 5'-GAGGGGCCATCCACAGTCT-TCT-3'.

Amplified products were electrophoresed on 1.5% agarose gel and then stained with ethidium bromide; 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 LPS (0.1 µg/mL)-activated monocytic THP-1 cells was used as a positive control. The experimental conditions and number of cycles of PCR were predetermined to ensure that the amount of MIP-1, IL-8, 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 (Corning Costar, Cambridge, MA). THP-1 cells were incubated with 200 nM phorbol myristate acetate (Sigma Chemical Co.) for 48 h to differentiate macrophage-like cells from monocytes (24). The cells were resuspended at 1.5 x 10⁶/mL in the presence or absence of dobutamine at various concentrations and then loaded into the upper chamber of the Micro Chemotaxis chamber. The chemoattractant MIP-1 (R&D Systems) (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 2 h at 37°C in a humidified atmosphere with 5% CO₂. After the 2-h incubation, the number of monocytes that migrated to the lower compartment was determined by counting the cells under light microscopy.

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 analyses.

	Results

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After 4 h of incubation, a minimal quantity of MIP-1 production by the THP-1 cells in the media (125 ± 65 pg/mL) and a high level (3860 ± 580 pg/mL) induced by LPS (0.1 µg/mL) was found. Dobutamine (1–100 µM) significantly suppressed LPS-induced MIP-1 production in a dose-dependent manner; the 50% effective concentration (EC₅₀) was 0.4 µM (Fig. 1). After 16 h of incubation, THP-1 cells produced a minimal amount of IL-8 (11 ± 12 pg/mL) in the medium without LPS, whereas LPS (0.1 µg/mL) induced a high level of IL-8 production (3790 ± 340 pg/mL). At concentrations of 1 to 100 µM, dobutamine significantly suppressed LPS-induced IL-8 production in a dose-dependent manner; the EC₅₀ was 0.8 µM (Fig. 2). Salbutamol had a suppressive effect similar to dobutamine on LPS-stimulated MIP-1 and IL-8 production; the EC₅₀ was 0.8 and 20 µM, respectively (Figs. 1 and 2). To investigate whether inhibition of MIP-1 and IL-8 by dobutamine occurred at the transcription level, we examined the content of MIP-1 and IL-8 mRNA in THP-1 cells incubated with LPS in the presence or absence of dobutamine and salbutamol. Both dobutamine and salbutamol (10 µM) caused decreases in MIP-1 mRNA levels determined at 2 h after LPS treatment (Fig. 3). However, IL-8 mRNA levels did not change after 10 µM dobutamine or salbutamol administration at 4 h after LPS treatment.

View larger version (14K): [in this window] [in a new window]   Figure 1. Effect of dobutamine and salbutamol on lipopolysaccharide (LPS)-induced macrophage inflammatory protein (MIP)-1 production by human monocytic THP-1 cells 4 h after LPS (0.1 µg/mL) administration. Percentage of inhibition is expressed as mean ± SEM of five or six separate experiments performed in duplicate. *P < 0.05; **P < 0.01; significant suppression of MIP-1 compared with LPS controls.

View larger version (15K): [in this window] [in a new window]   Figure 2. Effect of dobutamine and salbutamol on lipopolysaccharide (LPS)-induced interleukin (IL)-8 production by human monocytic THP-1 cells 16 h after LPS (0.1 µg/mL) administration. Percentage of inhibition is expressed as mean ± SEM of five or six separate experiments performed in duplicate. *P < 0.05; **P < 0.01; significant suppression of IL-8 compared with LPS controls.

View larger version (33K): [in this window] [in a new window]   Figure 3. Effect of dobutamine and salbutamol on macrophage inflammatory protein (MIP)-1 and interleukin (IL)-8 messenger RNA expression. Human monocytic THP-1 cells were stimulated with lipopolysaccharide (LPS; 0.1 µg/mL), with medium alone (control; Con), or with LPS with dobutamine or salbutamol (0.1 µM [L+DB0.1/L+SA0.1], 1 µM [L+DB1/L+SA1], or 10 µM [L+DB10/L+SA10]). Reverse transcriptase-polymerase chain reaction (RT-PCR) with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and MIP-1 and IL-8 primers was performed on total RNA extracts 2 and 4 h, respectively, after the initiation of culture; b.p. = base pairs.

View larger version (12K): [in this window] [in a new window]   Figure 4. Effect of dobutamine on macrophage inflammatory protein (MIP)-1-induced THP-1 cell-differentiated macrophage chemotaxis. THP-1 monocytic cells were pretreated with phorbol myristate acetate to differentiate them into macrophages. Then they were transferred to the upper compartment of a Micro Chemotaxis chamber (Corning Costar, Cambridge, MA) and incubated with vehicle or increasing concentrations of dobutamine at 37°C for 2 h. MIP-1 (10 nM) was added to the lower compartment. The number of differentiated monocytes that migrated to the lower compartment was counted under light microscopy. Percentage of inhibition is expressed as mean ± SEM of four separate experiments performed in duplicate. **P < 0.01 compared with MIP-1-stimulated THP-1 cells.

	Discussion

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Because dobutamine is a ß₁-adrenergic receptor agonist, to determine whether ß₂-specific receptor stimulation could also inhibit MIP-1 or IL-8 production, the effect of salbutamol (a ß₂ agonist) was studied and compared with that of dobutamine. Salbutamol had a suppressive effect similar to that of dobutamine on MIP-1 and IL-8 production. These results suggest that either ß₁ or ß₂ receptor activation may independently inhibit the MIP-1 or IL-8 production response to LPS in monocytes. The mechanism of action of ß-agonists on cytokine production has been studied in considerable detail. Activation of ß₁ or ß₂ receptors results in a highly specific activation of adenylate cyclase and an increase in the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP); cAMP is the major second messenger of ß-receptor activation. We believe that the attenuating effect of dobutamine and salbutamol on MIP-1 and IL-8 release is mainly due to ß-adrenoreceptor action, for at least two reasons. First, a number of studies report antiinflammatory properties of ß-adrenoreceptors (30), and second, it is reported that ß₁ and ß₂ subtypes are primarily of ß-adrenergic receptors in human THP-1 cells (31). Furthermore, we found that dobutamine inhibited LPS-induced MIP-1 mRNA expression, suggesting that it might act at the transcriptional level in human monocytic THP-1 cells. Nonetheless, LPS-induced IL-8 mRNA expression did not change after dobutamine treatment. Thus, the inhibition of IL-8 production might act at a posttranscriptional level.

Chemokines are the major regulatory proteins of leukocyte recruitment and activation in inflammatory disorders. Leukocyte responses to chemokines include chemotaxis, shape change, integrin- and selectin-mediated adhesion, exocytosis of granule enzymes, and the respiratory burst (32). It has been demonstrated that IL-8 induces neutrophil chemotaxis and MIP-1 induces macrophage chemotaxis (7). In this study, THP-1 differentiated macrophage migration induced by MIP-1 was demonstrated, and this chemotaxis was inhibited by dobutamine in a dose-dependent manner. This result suggests that dobutamine might suppress the recruitment and activation of leukocytes.

After traumatic injury or sepsis, plasma levels of several proinflammatory cytokines, including MIP-1 and IL-8, are significantly increased (17,33). Moreover, increased levels of IL-8 are correlated with the severity and survival of patients (16,19). Knowledge of the effects of dobutamine on chemokine production may be important for understanding the interactions between dobutamine and chemokine-mediated inflammation. Moreover, in patients with sepsis or septic shock, dobutamine treatment is frequently given in these patients with hemodynamic instability. We demonstrate here that dobutamine suppresses LPS-induced production of MIP-1 and IL-8 in human monocytes. Further studies are warranted to establish the effects of dobutamine on MIP-1 and IL-8 production during the inflammatory response of septic patients.

In conclusion, excessive release of chemokines from monocytes stimulated with LPS mediates the pathophysiologic manifestation of septic shock. In this study, we demonstrated that dobutamine, a ß₁-adrenergic agonist, inhibits chemotaxis and LPS-induced MIP-1 and IL-8 production by human THP-1 monocytic cells. The site of this regulation is at the transcriptional level for MIP-1 and might be at the posttranscriptional level for IL-8.

	Acknowledgments

 
Supported by grants from 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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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Li, C.-Y. Articles by Ho, S.-T. Search for Related Content PubMed PubMed Citation Articles by Li, C.-Y. Articles by Ho, S.-T. Related Collections Critical Care Pharmacology