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Anesth Analg 2004;98:1767-1772
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000112310.93297.AF

ECONOMICS, EDUCATION, AND HEALTH SYSTEMS RESEARCH

A Platelet Activating Factor Receptor Antagonist Inhibits Cytokine Production in Human Whole Blood by Bacterial Toxins and Live Bacteria

Masanori Ogata, MD, Koichiroh Nandate, MD, Takashi Kawasaki, MD, Chika Kawasaki, MD, Masayuki Ozaki, MD, and Akio Shigematsu, MD

From the Department of Anesthesiology, University of Occupational and Environmental Health, Japan

Address correspondence and reprint requests to Masanori Ogata, MD, Department of Anesthesiology, University of Occupational and Environmental Health, 1–1 Iseigaoka, Yahatanishiku, Kitakyushu 807–8555, Japan. Address email to mogata{at}med.uoeh-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We previously reported that a platelet-activating factor receptor (PAFR) antagonist (TCV-309) suppressed lipopolysaccharide (LPS)-induced mortality and tumor necrosis factor (TNF) production in mice. However, the effect of TCV-309 on cytokine production induced by Staphylococcus enterotoxin B (SEB) or live bacteria has not been reported. In this study we investigated the effect of TCV-309 on cytokine production in human whole blood induced by LPS, SEB, and both Gram-positive and -negative bacteria. Human whole blood diluted 5:1 (980 µL) was placed in the wells of a 24-well plate. Ten microliters of LPS, SEB, Escherichia coli O18 K+, or Staphylococcus aureus were added to each well. After incubation at 37°C for 6 h, TNF, interleukin (IL)-6, and IL-8 in the culture medium were measured. TCV-309 did not affect the growth of either E. coli or S. aureus bacteria in the culture medium for the 6 h incubation. LPS, SEB, and both E. coli and S. aureus induced TNF, IL-6, and IL-8 in human whole blood. TCV-309 significantly inhibited the production of TNF, IL-6, and IL-8 induced by LPS, SEB, and bacteria. A PAFR antagonist suppressed cytokine production induced by LPS, SEB, and both Gram-positive and -negative bacteria in human whole blood. A PAFR plays an important role of producing proinflammatory cytokines induced by both toxins and live bacteria.

IMPLICATIONS: The platelet-activating factor receptor plays an important role in producing proinflammatory cytokines induced by bacterial toxins, such as lipopolysaccharide,Staphylococcus enterotoxin B, and live Gram-positive and Gram-negative bacteria.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Annually, more than half a million people in the United States develop sepsis, and the mortality rate is approximately 30% (1). Both Gram-positive and Gram-negative bacteria evoke a state of shock that is characterized by cardiovascular collapse, multiple organ failure, and frequent mortality. Approximately 50% of all cases of septic shock are associated with Gram-positive bacteria (2,3).

Tumor necrosis factor (TNF), interleukin (IL)-8, and IL-6 have been implicated as important mediators of the lethal effect of bacterial infection. Lipopolysaccharide (LPS) induces proinflammatory cytokines, as do other components of the bacterial cell wall, such as peptidoglycans. Staphylococcal enterotoxins (SE) and toxic shock syndrome 1 are well-known enterotoxins produced by Gram-positive bacilli. These toxins function as superantigens that activate T cells, monocytes, and macrophages without the internalization and proteolysis required by conventional antigens, and result in the synthesis of a variety of cytokines, such as TNF, IL-2, IL-6, and IL-8 (4–6).

We previously reported that a novel platelet-activating factor receptor (PAFR) antagonist (TCV-309) suppressed LPS-induced mortality and TNF production in mice (7). It has been reported that PAFR antagonists failed to improve the clinical outcome in patients with severe sepsis (8). Therefore, we wondered whether PAFR antagonists substantially inhibit the cytokine production induced in human whole blood by bacterial toxins or live bacteria. There are no reports on the effects of PAFR antagonists on the induction of cytokine production by live bacteria or bacterial toxins, such as SEB.

This study investigated the effect of TCV-309 on the induction of cytokine production in human whole blood by bacterial toxins, such as LPS and SEB, and live bacteria, such as E. coli O18K+ and S. aureus.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Phenol-extracted Escherichia coli (0127: B8) LPS was purchased from Difco Laboratories (Detroit, MI). Recombinant human TNF-{alpha} was purchased from Genzyme CO (Cambridge, MA). TCV-309, a selective PAFR antagonist, was a kind gift from Takeda Phamaceutical CO, Osaka, Japan.

E. coli O18 K+, a smooth encapsulated strain, and S. aureus were provided by S. Warren. One day before the experiments, one colony of each bacterium was inoculated in trypticase soy broth (TSB), and incubated overnight at 37°C. The next day, log-phase growth of the bacteria was initiated by adding additional TSB and incubating the culture for an additional 2.5 h, until reaching an OD550 of 0.8. The bacteria were then washed twice and suspended in normal saline. The appropriate concentration of bacteria for inoculation was obtained by diluting the suspension in saline until obtaining a spectrophotometric reading that corresponded to the necessary number of colony-forming units per milliliter based on a standard curve.

After approval from our Human Investigation Committee, informed consent was obtained from seven healthy male volunteers who were not taking any medication. Blood samples were drawn into tubes containing heparin and diluted with 5 volumes of Roswell Park Memorial Institute (RPMI) 1640 (Nissui Pharmaceutical, Tokyo, Japan) (9). The diluted blood (980 µL per well) was placed in 24-well tissue culture plates (Becton Dickinson, Franklin Lakes, NJ).

After adding different doses (0–10 µM) of TCV-309 to each well, the whole blood was stimulated with LPS, SEB, or bacteria (105/mL). Then, the blood was incubated for 6 h at 37°C in a 95% air/5% CO2 incubator. After incubation, the blood was centrifuged at 700g for 10 min to remove blood cells and bacteria. Supernatant samples were collected and stored at –80°C until assayed. For selected experiments, aliquots were removed, serially diluted, and plated overnight at 37°C on soybean casein digest agar. Bacterial viability was measured as the number of colony-forming units on the plates.

The L929 cell cytotoxic assay was used to determine the plasma TNF-{alpha} activity, as described previously (10). Briefly, L929 cells in RPMI 1640 medium containing 5% fetal calf serum (FCS) were seeded at 3 x 105 cells/well in 96-well flat-bottomed microtiter plates (Becton Dickinson) and incubated overnight at 37°C in an atmosphere of 5% CO2 in air. Serial 1:2 dilutions of samples were made in the just-described medium containing 1 mg/mL actinomycin D (Banyu Pharmaceutical, Tokyo, Japan), and 0.1 mL of each dilution was added to different wells. The next day, cell survival was assessed by fixing and staining the cells with crystal violet (0.2% in 20% methanol), and 1% sodium dodecyl sulfate was added to each well to solubilize the stained cells. The absorbance of each well was determined at 490 nm using a microplate reader (Bio-Rad Laboratories, Richmond, CA). TNF activity was expressed in units per milliliter, which is the reciprocal of the dilution necessary for 50% lysis of the cells.

The plasma IL-6 concentration was measured in duplicate using a commercially available enzyme-linked immunoassay (IL-6 Enzyme Immunoassay Kit; Advanced Magnetics, Cambridge, MA). The intra- and interassay precision was 9 and 6%, respectively, at an IL-6 concentration of 88 pg/mL. The plasma IL-8 concentration was measured in duplicate using an enzyme-linked immunoassay (IL-8 Enzyme Immunoassay Kit, Advanced Magnetics). The intra- and interassay precision was 7% and 4%, respectively, at an IL-8 concentration of 76 pg/mL. According to the manufacturer, cross-reactivity with other cytokines is negligible in both assays.

To assess the effect of TCV-309 on leukocyte viability, different doses (0–10 µM) of TCV-309 were added to diluted human whole blood and incubated for 6 h at 37°C in a 95% air/5% CO2 incubator. After incubation, the blood was centrifuged at 700g for 10 min. Buffy coats were isolated and the red blood cells were lysed with NH4Cl. The white blood cells were resuspended in RPMI 1640 medium containing 5% FCS and the cells were stained with 0.2% trypan blue. The cell survival rate was assessed under a microscope.

All data are presented as the mean ± SEM. The paired Student’s t-test was used to compare values with the control value. A significant difference was presumed for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In a preliminary experiment, whole blood was stimulated using different doses of LPS and SEB. As shown in Figure 1, the TNF production plateaued at LPS and SEB concentrations exceeding 10 ng/mL and 10 µg/mL, respectively, for a 6-h incubation. Therefore, we used these concentrations as the stimulatory concentrations of LPS and SEB in this study. After adding different doses of TCV-309, whole blood was stimulated with LPS (10 ng/mL) for 6 h. Figure 2 shows the effect of TCV-309 on LPS-induced cytokine production. At doses of 2.5 µM and larger, TCV-309 significantly inhibited LPS-induced TNF production as compared with the control. LPS-induced IL-6 and IL-8 production was suppressed at doses of 5 and 10 µM and larger, respectively. Leukocyte viability was not influenced by the dose (0~10 µM) of TCV-309.



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  		Figure 1. Tumor necrosis factor (TNF) production in human whole blood by Lipopolysaccharide (LPS) (A) and Staphylococcal enterotoxin B (B). Values are expressed as mean ± SEM (n = 5).

 


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  		Figure 2. Effect of TCV-309 on lipopolysaccharide (LPS) induced tumor necrosis factor (TNF)(A), interleukin-6(B), and interleukin-8(C) production. After TCV-309 (0~10 µM) was added, human whole blood was stimulated by LPS and incubated for 6 h. Values are expressed as mean ± SEM (n = 7). *P < 0.05, **P < 0.01 compared with control.

 
The SEB-induced cytokine production is shown in Figure 3. After adding different doses of TCV-309, whole blood was stimulated with SEB (10 µg/mL) for 6 h. Doses of 1.25, 5, 10 µM and larger of TCV-309 inhibited SEB-induced production of TNF, IL-6, and IL-8, respectively, in comparison with the control.



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  		Figure 3. Effect of TCV-309 on Staphylococcal enterotoxin B (SEB) induced tumor necrosis factor (TNF)(A), interleukin-6(B), and interleukin-8(C) production. After TCV-309 (0~10 µM) was added, human whole blood was stimulated by SEB and incubated for 6 h. Values are expressed as mean ± SEM (n = 7). *P < 0.05, **P < 0.01 compared with control.

 
The diluted human whole blood was stimulated with mid-log phase growing E. coli 018 K+ or S. aureus at a concentration of 105/mL. The concentrations of both E. coli O18 K+ and S. aureus increased to approximately 107/mL in whole blood with TCV-309 (0–10 µM) for a 6-h incubation (data not shown). The TCV-309 did not affect the growth of either bacterium.

After adding different doses of TCV-309, the whole blood was stimulated with E. coli (105/mL) for 6 h. Figure 4 shows the effect of TCV-309 on cytokine production induced by E. coli O18 K+. When the blood was incubated for 6 h, E. coli O18 K+ induced TNF (2560 ± 570 U/mL), IL-6 (234 ± 50 pg/mL), and IL-8 (1175 ± 48 pg/mL). At TCV-309 concentrations of 1.25 µM and larger, the induction of TNF by E. coli O18 K+ was inhibited significantly. IL-8 and IL-6 were inhibited at TCV-309 concentrations of 2.5 and 10 µM and larger, respectively.



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  		Figure 4. Effect of TCV-309 on E.coli:O18K+ induced tumor necrosis factor (TNF)(A), interleukin-6(B), and interleukin-8(C) production. After TCV-309 (0~10 µM) was added, human whole blood was stimulated by E.coli:O18K+ and incubated for 6 h. Values are expressed as mean ± SEM (n = 7). *P < 0.05, **P < 0.01 compared with control.

 
After adding different doses of TCV-309, whole blood was stimulated with S. aureus for 6 h (Fig. 5). S. aureus induced TNF (846 ± 130 U/mL), IL-6 (203 ± 38 pg/mL), and IL-8 (505 ± 110 pg/mL). TCV-309 concentrations of 1.25 µM and larger inhibited the induction of TNF and IL-8 by S. aureus, whereas IL-6 was suppressed at concentrations of 2.5 µM and larger.



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  		Figure 5. Effect of TCV-309 on Staphylococcus aureus induced tumor necrosis factor (TNF)(A), interleukin-6(B), and interleukin-8(C) production. After TCV-309 (0~10 µM) was added, human whole blood was stimulated by S. aureus and incubated for 6 h. Values are expressed as mean ± SEM (n = 7). *P < 0.05, **P < 0.01 compared with control.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrated that a PAFR antagonist (TCV-309) significantly suppressed the production of inflammatory cytokines (TNF, IL-6, and IL-8) induced in human whole blood by LPS, SEB, and live E. coli O18 K+ and S. aureus.

Several studies have shown that PAFR antagonists suppress the LPS-induced production of TNF, superoxide, and nitric oxide in vitro (11–13). Previously, we reported that TCV-309 inhibited the increase of serum TNF levels and mortality induced by LPS in mice (7). In this study, we showed that a PAFR antagonist (TCV-309) suppressed the production of TNF, IL-6, and IL-8 induced by LPS, SEB, E. coli O18 K+, and S. aureus. By contrast, Cauwels et al. (14) reported that a PAFR antagonist (L659,989) had no effect on the cytokine production induced by LPS and or Streptococcus pneumonia in human whole blood. We postulate that differences in the PAFR antagonist and bacteria caused the different results.

The mechanism by which the PAFR antagonist inhibits LPS-induced cytokine production is not known. It has been reported that PAFR antagonists inhibit LPS-induced TNF mRNA expression (15). The effect of a platelet-activating factor (PAF) depends on the intracellular calcium concentration. Inhibition of the calcium flux attenuates the effects of PAF on LPS-stimulated macrophages (16). Nakamura et al. (17) reported that LPS transduces calcium ion signaling via a PAFR using cloned PAF receptors expressed in Xenopus oocytes and Chinese hamster ovary cells. Ishii et al. (18) reported that PAFR–/– mice failed to acquire resistance to endotoxin in comparison with PAFR+/+ mice. Endotoxin induced macrophages from PAFR–/– mice to produce TNF and IL-6 to the same extent as in those from wild-type mice. These results suggest that the PAFR is not an LPS receptor but plays an important role in LPS-induced transcriptional change and calcium ion signaling.

SEB functions as a superantigen and has the ability to activate T cells, binding major histocompatibility complex class II receptors, such as those on monocytes, and the T-cell receptor of T lymphocytes expressing specific Vß chains (4). Ours is the first report that a PAFR antagonist (TCV-309) suppresses SEB-induced cytokine production in human whole blood. One study demonstrated that SEB induced TNF-{alpha} production in T cells, but not in monocytes, and that protein kinase C activation plays a critical role in this (19). We have not studied the mechanism by which PAFR antagonists inhibit SEB-induced cytokine production. Further studies are needed to answer this question.

The PAFR exists in platelets, neutrophils, monocytes, macrophages, and endothelial cells (18,20). The PAFR is a member of the G-protein-coupled receptor superfamily, which is characterized by seven transmembrane domains. Activation of the PAFR leads to the activation of several signal-transduction pathways (21,22). Our data demonstrated that the PAFR on the cell membrane interacts with both toxins, such as LPS and SEB, and with bacteria, such as E. coli O18 K+ and S. aureus, to induce inflammatory signal transduction. It has been reported that PAF itself activates NF-{kappa}B, inducing cytokine production and PAFR expression (23,24). Recently, Pacheco et al. (25) reported that LPS-induced lipid body formation was inhibited by a PAFR antagonist, suggesting a role for endogenous PAF. We postulate that PAFR antagonists block the biological effects of endogenous PAF induced by bacteria or bacterial toxins. Therefore, PAFR antagonists may attenuate the synergism between endogenous PAF and bacterial toxins, ultimately inhibiting inflammatory cytokine signal transduction.

Our study demonstrated that PAFR antagonists suppress the induction of proinflammatory cytokines in human whole blood by bacterial toxins or live bacteria. However, the PAFR antagonist did not influence bacterial growth in our study. It has been reported that the PAFR is important for phagocytosis and bacterial anchoring to human cells (26–29). Recently, it was found that Klebsiella pneumonia induced lethality in PAFR-deficient mice earlier than in wild-type control mice, suggesting that PAF plays a protective role during infection (30). The inhibition of bacterial phagocytosis and killing may be one of the mechanisms that prevent PAFR antagonists from improving the clinical outcome in septic patients. Further study is needed to evaluate this hypothesis.

In conclusion, we found that a PAFR antagonist (TCV-309) inhibited the induction of cytokine production in human whole blood not only by bacterial toxins, such as LPS and SEB, but also by live bacteria, such as E. coli O18 K+ and S. aureus, suggesting that PAFR is engaged in cytokine signal transduction induced by both toxins and live bacteria.


   Acknowledgments
 
Supported, in part, by departmental funding and a grant-in-aid for scientific research [(B) (2)14370499, 15659431] from the Ministry of Education, and Culture of Japan.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 26, 2003.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press