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Originally published online as doi:10.1189/jlb.1103595 on March 23, 2004

Published online before print March 23, 2004
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(Journal of Leukocyte Biology. 2004;75:1111-1115.)
© 2004 by Society for Leukocyte Biology

Oxygen radical-induced natural killer cell dysfunction: role of myeloperoxidase and regulation by serotonin

Åsa Betten*,1, Claes Dahlgren{dagger}, Ulf-Henrik Mellqvist{ddagger}, Svante Hermodsson* and Kristoffer Hellstrand*

* Departments of Clinical Virology,
{dagger} Rheumatology and Inflammation Research, and
{ddagger} Hematology, Göteborg University, Sweden

1 Correspondence: Department of Virology, Göteborg University, Guldhedsgatan 10 B, S-413 46 Göteborg, Sweden. E-mail: Aasa.Betten{at}microbio.gu.se


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Natural killer (NK) cells are functionally suppressed and induced to apoptosis by reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs). These inhibitory events are reversed by the biogenic amine serotonin. MPs generate hydrogen peroxide (H2O2), which is processed further by myeloperoxidase (MPO) to even more toxic compounds. Earlier studies suggest that serotonin scavenges MP-derived oxygen radicals generated by the MPO-H2O2 system. These findings led us to explore the capability of MPO-deficient MPs to induce NK cell dysfunction. We show that MPs recovered from subjects with MPO deficiency trigger inhibition of NK cells. In addition, MPs recovered from healthy subjects conveyed suppression of NK cells in the presence of the MPO inhibitor ceruloplasmin. We conclude that ROS-dependent inhibition of NK cell function is unrestricted by the availability of MPO-derived oxygen radicals and that the protecting properties of serotonin may operate in the absence of functional MPO. Our data suggest a complex mechanism of MP-induced NK cell inhibition, which comprises the generation of interchangeable oxygen radicals.

Key Words: reactive oxygen species • NK cells • mononuclear phagocytes • MPO-deficient


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Natural killer (NK) cells are a subset of lymphocytes that have been suggested to play a significant role in the innate host defense by exerting antibody-dependent and -independent cytotoxicity against malignant and virus-infected cells [1 2 3 ]. In previous studies, we have demonstrated that mononuclear phagocytes (MPs) recovered from healthy subjects are strongly inhibitory for cytotoxic lymphocytes. Thus, NK cells and several phenotypes of T cells become dysfunctional after contact with autologous MPs and eventually enter a suicidal program of apoptosis [4 5 6 7 8 9 ]. NK cells are, for unknown reasons, more sensitive to this suppressive signal than other subsets of cytotoxic lymphocytes [8 , 10 ].

Studies on the mechanisms responsible for the triggering of lymphocyte dysfunction by MPs have demonstrated a pivotal role for reactive oxygen species (ROS). The assembly and activation of a membrane-bound enzymatic complex, the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which reduces molecular oxygen to superoxide anions (O2–) and hydrogen peroxide (H2O2), generate these toxic, oxygen-derived compounds [11 , 12 ]. In an additional pathway of radical formation, MPs transform H2O2 to even more toxic agents, including hypohalids such as hypochloric acid. This reaction is catalyzed by myeloperoxidase (MPO), an enzyme found primarily in cytoplasmic granules of MPs and neutrophilic granulocytes [13 ]. Evidence for the involvement of NADPH oxidase-derived ROS in the inactivation and apoptotic killing of NK cells stems from the finding that MPs from patients with chronic granulomatous disease (a genetically determined, functional defect of the NADPH oxidase) do not suppress NK cell function or viability [7 ]. Also, scavengers of ROS and inhibitors of NADPH oxidase activity reverse the MP-induced suppression [8 , 14 ].

These mechanisms of NK cell inhibition have been ascribed a role in the phenomenon of "immune escape," i.e., the relative inefficiency of lymphocyte-mediated immunity at the site of malignant tumor growth and in chronically infected tissues [15 , 16 ]. Understanding the mechanisms and regulation of ROS-mediated inactivation of lymphocytes may therefore have therapeutic implications.

We have reported earlier that serotonin, a biogenic amine released from activated platelets in inflammatory and ischemic tissues, efficiently protects NK cells from functional suppression conveyed by MPs [17 , 18 ]. Serotonin is a specific scavenger of peroxidase-derived radicals, as suggested by the finding that serotonin protects NK cells from suppression induced by H2O2 + MPO but not by H2O2 alone [19 ]. These results thus imply indirectly that MPO and its products play a role in the MP-mediated, ROS-dependent suppression of NK cells.

In this study, we have used MPs from MPO-deficient subjects and agent, which inhibit MPO activity, to further elucidate the mechanisms responsible for the ROS-mediated NK cell inhibition with emphasis on the putative role of MPO. Our data suggest that several species of oxygen radicals, some of which can be formed independently of MPO, suppress NK cell function. The results also imply that the ROS-scavenging activity of serotonin has a broader specificity than earlier anticipated.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Separation of mononuclear cells (MNC)
MNC were prepared from peripheral venous blood, obtained as buffy coats (65 ml) from healthy blood donors at the Blood Centre, Sahlgren’s Hospital (Göteborg, Sweden). MPO-deficient MNC were obtained from peripheral whole blood (100 ml) drawn from donors identified by the lack of myelo- and eosinophil peroxidase activity, analyzed by use of a Bayer Technicon H2 instrument. The blood was mixed with 92.5 ml Iscoves’ medium, 35 ml 6% Dextran, and 7.5 ml acid citrate dextrose (ACD).

After incubation for 15 min at room temperature, supernatants were removed and layered on top of a Ficoll-Hypaque column (Lymphoprep, Nyegaard, Norway). MNC were collected at the interface after centrifugation at 380 g for 15 min, washed twice in phosphate-buffered saline, and resuspended in Iscoves’ medium supplemented with 10% human AB+ serum. During all further separation of cells, the cell suspensions were kept in siliconized test tubes (Vacuette, Greiner, Stockholm).

The MNC were further separated into lymphocytes and MPs using the counter-current centrifugal elutriation technique, as described in detail elsewhere [20 ]. Briefly, the MNC were resuspended in elutriation buffer containing 0.5% bovine serum albumin (BSA) and 0.1% EDTA in buffered NaCl and fed into a Beckman J2-21 ultracentrifuge with a JE-6B rotor at 2100 rpm. A fraction with >90% MPs was obtained at a flow rate of 18 ml/min. A lymphocyte fraction enriched for NK cells (CD3{varepsilon}–/56+ phenotype) and T cells (CD3{varepsilon}+/56–) was recovered at flow rates of 14–15 ml/min. The latter fraction consisted of CD3{varepsilon}–/56+ NK cells (45–50%), CD3{varepsilon}+/56– T cells (35–40%), CD3{varepsilon}–/56– cells (5–10%), and CD3{varepsilon}+/56+ cells (1–5%) with less than 3% contaminating MPs, as judged by flow cytometry.

Target cells and microcytotoxicity assay
K562 cells, an NK cell-sensitive cell line originating from a patient with chronic myelogenous leukemia in blast crisis [8 ], were used as target cells. The K562 cells (5–10x106 cells/ml) were loaded with 51Cr at a concentration of 150 µCi/ml cell suspension for 2 h at 37°C. Excess 51Cr was removed by centrifugation x4, and target cells were resuspended in culture medium. Finally, 10,000 51Cr-loaded target cells in 50 µl portions were added to the mononuclear cells in 96-well microplates (Nunc, Roskilde, Denmark).

Lymphocytes were incubated in microplates (100,000 cells/well in 200 µl) with or without autologous MPs (5–100,000 cells/well) for 16 h at 37°C with labeled target cells. All assays were done in quadruplicates or sextuplicates. The compounds were added at the onset of incubation. After incubation at 37°C for 16 h, supernatant fluids were collected by a tissue-collecting system (Amersham Pharmacia Biotech AB, Uppsala, Sweden) and were assayed for radioactivity in a {gamma}-counter. Maximum 51Cr release was determined in target cell cultures treated with Triton X-100. NK cell cytotoxicity was calculated using the formula: 100 x [(experimental 51Cr release–spontaneous release)/(maximum release–spontaneous release)] = cell lysis %. In accordance with earlier studies [7 , 10 ], >90% of the lymphocyte cytotoxicity against K562 cells was depleted by the removal of CD56+ NK cells (by use of anti-CD56-coated beads as described in refs. [7 , 10 ]); in contrast, the removal of CD3+ T cells (by use of anti-CD3-coated beads) from the effector lymphocyte preparations did not reduce cytotoxicity significantly.

Determination of NADPH oxidase activity
MP superoxide production was determined using an isoluminol-amplified chemiluminescence (CL) technique [21 , 22 ]. Samples containing 500,000 elutriated MPs in Krebs-Ringer glucose buffer (KRG) were incubated in a six-channel Berthold Biolumat LB 9505 at 37°C. Release of O2– was measured in the presence of 10 µg/ml isoluminol and 4 U/ml horseradish peroxidase (HRP) or 2.5 µg/ml MPO. The radical release was determined in the presence or absence of the MPO inhibitors ceruloplasmin or Na-azide, and the NADPH oxidase was activated by the addition of 0.1 µM formylmethionyl-leucyl-phenylalanine (fMLF) for induction of extracellular radical production.

MPO assay, peroxidase activity
MPO content in MPs was measured as enzyme activity. The peroxidase substrate 1,2-phenylenediamine dihydrochloride (OPD) was dissolved according to the manufacturer’s directions and mixed with H2O2 immediately before use. MPs (107/ml) from three controls and two MPO-deficient subjects were lysed with 0.1% Triton X-100 in KRG on ice for 10 min. The samples were centrifuged, and 100 µl of the supernatant was mixed with 200 µl peroxidase substrate in a 96-well plate and incubated for 1.5 h at room temperature. The absorbance was measured at 450 nm, and the MPO level of the samples was interpolated from a MPO standard curve.

Compounds
Serotonin hydrochloride, isoluminol, and fMLF were purchased from Sigma Chemical Co. (St. Louis, MO). MPO was kindly provided by Inge Olsson (Lund University, Lund, Sweden), HRP was from Boehringer-Mannheim (Mannheim, Germany), and dextran was from Kabi-Pharmacia (Stockholm, Sweden). H2O2 and EDTA (KEBOLab, Göteborg, Sweden), ACD (Baxter, Deerfield, IL), 51Cr (Amersham Pharmacia Biotech AB), BSA (ICN Biomedicals, Inc., Aurora, OH), ceruloplasmin (Calbiochem, La Jolla, CA), and OPD (Dako, Glostrup, Denmark) were used. All compounds were dissolved in Iscoves’ culture medium or KRG, depending on the purpose.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of serotonin on NK cell function
NK cell function was measured as specific cytotoxicity against K562 erythroleukemic target cells. In accordance with earlier findings [10 , 14 ], the ability of NK cells to lyse these target cells was strongly suppressed in the presence of autologous MPs. Also in accordance with previous findings [19 ], NK cells were efficiently protected from the MP-induced inhibition by serotonin (Fig. 1A ). Serotonin also protected NK cells, in the absence of MPs, from inhibition induced by concomitant treatment with H2O2 and MPO but did not protect NK cells from H2O2 without MPO (Fig. 1B) . These data not only suggested that serotonin protects NK cells from ROS produced by MPs by scavenging one or more peroxidase-derived radicals but also that MPO products contribute significantly to the MP-induced NK cell inhibition.



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  		Figure 1. Serotonin protects NK cells from functional inhibition induced by MPs or H2O2 and MPO. (A) NK cell-enriched lymphocytes (1x105 cells/well) were assayed for NK cell cytotoxicity against 51Cr-labeled K562 (1x104 cells/well) target cells. NK cells were incubated in the absence or presence of MPs (1x105 cells/well) for 16 h at 37°C. Control cells were treated with culture medium (open bars), and serotonin (100 µM, solid bars) was added at the onset of incubation. Data are cell lysis (%) ± SEM of sextuplicate determinations, and similar results were obtained in eight different experiments. (B) The cell cultures were treated with culture medium (control, open circles), serotonin (100 µM, solid triangles), MPO (2.5 µg/ml, open triangles), or serotonin + MPO (solid circles), and the final concentrations of H2O2 are indicated on the abscissa. All compounds were added at the onset of incubation, and data are % cell lysis (mean±SEM of quadruplicate determinations). Inset shows NK cell inhibition of target cell lysis induced by 150 µM H2O2, and data are mean values ± SEM of separate experiments using blood from different blood donors. For statistical analysis, Student’s t-test was used (**, P<0.01, n=11).

 
Effects of a MPO inhibitor on ROS-induced NK cell dysfunction
Next, we investigated the degree of MP-induced NK cell inhibition in the presence of a MPO inhibitor, ceruloplasmin [23 ]. To verify that ceruloplasmin specifically inhibited MPO activity in human MPs, we used a peroxidase-dependent, amplified CL system, a method normally conducted with an excess of HRP [21 , 22 ]. When the MP NADPH oxidase was triggered by the chemotactic peptide fMLF, a rapid and intense radical release was registered, reaching a peak of activity after 1–2 min. The presence of ceruloplasmin did not affect the amount of detected radicals (Fig. 2A ), suggesting that the inhibitor did not affect the cellular production of ROS directly. When we replaced the standard amplifying peroxidase (HRP) by MPO in this assay, the presence of ceruloplasmin strongly reduced the amount of radicals detected (Fig. 2B) .



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  		Figure 2. Ceruloplasmin inhibits MPO-mediated radical formation in MPs. NADPH oxidase activity in human neutrophils was induced by the chemotactic peptide fMLF (0.1 µM). CL responses are measured in the presence of isoluminol (a non-cell-permeable CL substrate; 10 µg/ml) and HRP (4U; A) or MPO (2.5 µg/ml; B) in the absence (open circles) or presence of the MPO inhibitors ceruloplasmin (25 µM, solid circles) or Na-azide (0.1 mM, solid triangles). The graphs are from one representative experiment, and similar results were obtained in five different experiments using different blood donors. Results are given in counts per minute (cpm).

 
From these experiments, it was concluded that ceruloplasmin inhibits MPO-catalyzed reactions in MPs efficiently and that this inhibition is selective with respect to the peroxidase species involved. Ceruloplasmin therefore appeared to be a suitable tool to investigate the role of MPO in the MP-induced inhibition of NK cell function. However, the presence of ceruloplasmin at concentrations clearly sufficient to inhibit MPO activity in the peroxidase-dependent CL model did not reverse or reduce the MP-induced NK cell inhibition (Fig. 3 ).



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  		Figure 3. MP-induced inhibition of NK cell cytotoxicity is unaffected by pharmacologic inhibition of MPO. NK cell-enriched lymphocytes were incubated in the absence (control, open circles) or presence of autologous MPs (solid circles) and were assayed for cytotoxicity against K562 target cells as described in Figure 1 . The cell cultures were treated with culture medium or various concentrations of the MPO inhibitor ceruloplasmin. Results are cell lysis % (mean±SEM of three separate experiments using blood from different blood donors).

 
MPO-deficient MPs induce NK cell suppression: reversal by serotonin
Taken together, these findings suggest on the one hand that MPO-derived radicals are of importance in ROS-mediated NK cell suppression but on the other hand that pharmacologic inhibition of MPO activity fails to inhibit MP-induced suppression. To further clarify the role of MPO in NK cell suppression, we investigated the NK cell-modulatory effects of MPs that constitutively lacked peroxidase activity. It was found that autologous MPs from MPO-deficient subjects (identified by the lack of MPO activity, analyzed by use of a Bayer Technicon H2 instrument) were as efficient in triggering NK cell inhibition as normal MPs. As was the case for normal MPs, the inhibition of NK cells induced by MPO-deficient cells was efficiently reversed by serotonin (Fig. 4 ).



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  		Figure 4. MPs from MPO-deficient subjects inhibit NK cell function. NK cell-enriched lymphocytes were incubated in quadruplicates in the absence (control, open bars) or presence of autologous MPs (solid bars) obtained from MPO-deficient subjects and assayed for cytotoxicity against K562 cells as described in Figure 1 . The cell cultures were treated with culture medium (control) or serotonin (100 µM). Results are cell lysis % (mean±SEM of five separate experiments using five MPO-deficient blood donors).

 
To rule out the possibility that the NK cell suppression mediated by the MPO-deficient MPs was mediated by minor amounts of MPO or other alternative sources of peroxidase activity such as eosinophil peroxidase, we double-checked two of the MPO-deficient blood donors for peroxidase activity. The MPO level of the two samples was found to be below the detection limit of our assay (<0.12 µg/5x105 cells), indicating that the suppressive effect seen was not a result of any peroxidase activity for which was unaccounted. In normal control MPs, a MPO level of 0.88 ± 0.28 µg/5 x 105 cells (n=3) was determined.

To further exclude a putative contribution by minute amounts of a peroxidase that may be present in MPs from MPO-deficient subjects, we analyzed the lowest amount of MPO required for serotonin to maintain its protective effect on ROS-mediated NK cell suppression. Serotonin protected the NK cells significantly from H2O2-induced suppression in the presence of 0.5 µg/ml MPO, whereas 0.1 µg/ml MPO was insufficient for NK cell protection (Fig. 5 ). As the peroxidase level in the MPO-deficient MPs was found to be <0.12 µg/5 x 105 cells, and the standard amount of MPs/well in the NK cell functional assay was five times lower, we concluded the conjectural peroxidase activity of the MPO-deficient subjects to be negligible.



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  		Figure 5. The lowest amount of MPO required for serotonin to maintain the reduction of NK cell cytotoxicity mediated by ROS. NK cell-enriched lymphocytes were assayed for cytotoxicity as described in Figure 1 . The cell cultures were treated with culture medium (control, open circles) or serotonin (100 µM) together with various concentrations of MPO (2.5 µg/ml, solid circles; 0.5 µg/ml, solid triangles; 0.1 µg/ml, solid squares). The final concentrations of H2O2 are indicated on the abscissa. All compounds were added at the onset of incubation, and data are cell lysis % (mean±SEM of quadruplicate determinations), and similar results were obtained in three experiments using blood from three different blood donors.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Earlier studies have shown that the formation and extracellular release of H2O2 by MPs are essential for the capacity of these cells to inhibit NK cells and other cytotoxic lymphocytes. This conclusion is based on the findings that catalase, which degrades H2O2 into oxygen and water, efficiently rescues NK cells from inhibition [7 , 8 ] and that treatment of NK cells with H2O2 at low concentrations mimics the inhibitory events induced by ROS-producing MPs. Therefore, H2O2 has been proposed as a conceivable effector molecule responsible for the inhibition [5 , 7 , 24 ].

Serotonin has been shown to protect NK cells efficiently against MP-induced, oxygen radical-mediated inhibition. In a previous study, we forwarded the hypothesis that this action of serotonin was explained by its scavenging of peroxidated radicals. Thus, serotonin protected NK cells only from inhibition induced by the combination of H2O2 and a peroxidase but not from H2O2 alone [19 ]. These results suggested that peroxidase-derived radicals, rather than H2O2 itself, were responsible for the MP-induced NK cell inhibition.

Therefore, this study was designed to determine the role of MPO, which is the main source of peroxidase activity in human MPs [13 ], and MPO-derived oxygen radicals in MP-induced NK cell inhibition. For this purpose, we used MPs recovered from subjects with a constitutive MPO deficiency and also blocked MPO activity using a MPO-specific inhibitor. Our data demonstrate that the NK cell inhibition induced by MPO-sufficient MPs is unaffected by the MPO inhibitor ceruloplasmin and that MPs recovered from MPO-deficient subjects are capable of conveying NK cell inhibition. Therefore, it is concluded that ROS-dependent inhibition of NK cells is not restricted by the availability of MPO-derived oxygen radicals. In addition, our finding that serotonin protected NK cells from suppression induced by MPO-deficient MPs suggests a broader specificity of the scavenging activity of serotonin than earlier anticipated.

Our results indicate the existence of at least three types of radicals that suppress NK cell function. First, H2O2 inhibits NK cell function and induces apoptosis in NK cells [7 , 8 ], a suppressive mechanism to which serotonin affords no protection. Second, the addition of MPO to H2O2 results in the generation of radicals that down-regulate NK cells, and serotonin efficiently protects NK cells from damage induced by MPO-dependent radicals [19 ]. Third, the results obtained from the MPO-deficient MPs suggest the existence of yet another not-identified, MPO-independent, and serotonin-sensitive oxygen radical, which inhibits NK cells.

These findings are suggestive of a complex system that generates a diversity of oxygen radicals, which can compensate for the lack of others [25 ], but the question of which radical species is the effector molecule involved in the MP-induced inhibition of NK cells remains unresolved. Our data suggest that although MPO-derived radicals do not play a major role, it is possible that the inhibition exerted by MPs is dependent on the formation of a peroxidated derivative of H2O2. This conclusion is based on the previous finding that serotonin is a scavenger not only of MPO-derived radicals but also of radicals generated from H2O2 by other sources of peroxidase [19 ]. Thus, we forward the hypothesis that a MPO-independent, serotonin-sensitive oxygen radical, which is formed after the peroxidation of H2O2, is pivotally involved in MP-induced inhibition of NK cell function.


   ACKNOWLEDGEMENTS
 
The Swedish Medical Research Council, the King Gustaf V Memorial Foundation, Maxim Pharmaceuticals, San Diego, and the Swedish Society against Cancer supported this work. We gratefully appreciate the technical assistance provided by Marie-Louise Landelius and Elisabeth Wallhult.

Received November 26, 2003; revised January 28, 2004; accepted February 9, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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J. Immunol., February 15, 2005; 174(4): 2235 - 2241.
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