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(Journal of Leukocyte Biology. 2001;69:414-418.)
© 2001 by Society for Leukocyte Biology

Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?

F. Caldefie-Chezet*, A. Poulin*, A. Tridon{dagger}, B. Sion{ddagger} and M-P. Vasson*

* Laboratoire de Biochimie, Biologie Moléculaire et Nutrition, EA 2416, Faculté de Pharmacie, Centre de Recherche en Nutrition Humaine, Clermont-Ferrand;
{dagger} Laboratoire d’Immunologie, Faculté de Pharmacie, Clermont-Ferrand; and
{ddagger} Laboratoire de Biologie du Développement, Faculté de Médecine, Clermont-Ferrand, France

Correspondence: F. Caldefie-Chézet, Laboratoire de Biochimie, Biologie Moléculaire et Nutrition, Faculté de Pharmacie, 28, place Henri-Dunant, B.P. 38. 63001 Clermont-Ferrand, Cedex 1, France. E-mail: Florence.caldefie-chezet{at}u-clermont1.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is well known that leptin, the ob gene product, is involved in the regulation of food intake and thermogenesis. Recent studies also demonstrate that leptin may be able to modulate functions of cells involved in nonspecific immune response such as phagocytosis and secretion of cytokines by macrophages. This and the prominent implication of polymorphonuclear neutrophils (PMNs) in infectious response suggested a possible role of leptin as a modulator of PMN functions. We detected a leptin receptor on the PMN membrane by immunocytochemistry with an anti-leptin receptor. Using chemiluminescence we then demonstrated that leptin enhances oxidative species production by stimulated PMNs. These results show for the first time that a functional leptin receptor is present on PMNs and that leptin may be able to influence their oxidative capacity.

Key Words: receptor • reactive oxygen species • bactericide


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Leptin, the ob gene product, is a 16-kDa protein essentially secreted from adipocytes [1 , 2 ]. Its crystal structure reveals a four-helix bundle similar to those found in the long-chain helical cytokine family [3 ]. After release into the circulation it crosses the blood-brain barrier and acts on the hypothalamus via the neuropeptide Y [4 ] to induce satiety [5 , 6 ]. It is also well known that this hormone regulates energy balance by increasing energy expenditure [7 8 9 10 ]. Recently, it has been suggested that leptin also plays an important role in the regulation of endocrine functions [3 ] (glucocorticoids, insulin, sex steroids). It also has metabolic effects, particularly on lipid and glucid metabolism [11 ].

Leptin receptor (OB-R) encodes five or more splice variants. It includes a form predicted to be soluble, several short forms with small intracellular domains, and one long form. The latter is highly homologous to the signaling domain of the type I cytokine receptor family and utilizes the JAK/STAT pathway for signal transduction [3 ]. All these forms share a constant extracellular domain [12 ]. They are expressed in several tissues, e.g., hypothalamus, brain, pituitary, thymus, heart, and lung [12 13 14 ], and in hematopoietic lineages, especially CD34+ cells [15 , 16 ].

It has recently been suggested that leptin may be active on immune function [17 ]. Lord et al. [18 ] demonstrated that falling leptin levels are responsible for diminished immune response. They report that lymphocytes express the leptin long-receptor isoform and that leptin promotes lymphocyte activity in vitro, in particular the responsiveness of naive T cell subsets [17 ]. Leptin influences nonspecific immune functions such as macrophage response: macrophages have been found to express membranal OB-R [16 ]. Loffreda et al. [19 ] demonstrated in vitro and in vivo an impaired phagocytosis and an abnormal cytokine gene expression in studies of rodents with genetic abnormalities in leptin or leptin receptors.

However, among cells of the nonspecific immune response, polymorphonuclear neutrophils (PMNs) play a major role. PMNs are directed toward infectious particles (chemotaxis), capture opsonized bacteria via opsonin receptors, phagocytize the captured bacteria, and kill them by reactive oxygen species (ROS) aggression [20 ].

Nevertheless, to our knowledge no evidence has yet been reported of the presence of OB-R or a leptin effect on human PMNs implicated in infectious response. We therefore set out to determine whether PMNs express leptin membrane receptor. For this purpose, we used an immunocytochemical technique with a polyclonal antibody directed against the extracellular constant domain of OB-R. This was done in comparison with circulating lymphocytes known to express membrane OB-R [16 ]. In a second step, we explored the potential effects of leptin on the oxidative response of PMNs to confirm that this leptin receptor was functional and determine whether leptin could modulate in vitro PMN functions directly.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All chemicals were purchased from Sigma (St. Quentin-Fallavier, France) except for human recombinant leptin and anti-leptin receptor (R & D, Abingdon, UK), and the Avidin/Biotin Blocking Kit and Vectastain® ABC systems, obtained from Vector Laboratories.

Blood from six (immunocytochemistry assay) or seven (chemiluminescence assay) healthy human volunteers was collected in sterile EDTA-treated tubes. Leukocytes were rapidly isolated by density gradient centrifugation. They were carefully layered on a double gradient of Ficoll-Hypaque (Histopaque® 1077 and 1119) with equal volumes [21 ]. After centrifugation (700 g, 30 min, 20°C), the Ficoll-Hypaque layers were aspirated, yielding a phase of PMNs (1.077 < density < 1.119 g/mL) and a phase of lymphocytes (1.024 < density < 1.077 g/mL). The cells were then washed with phosphate-buffered saline (PBS, pH 7.4, 150 mM), centrifuged, and resuspended in 1 mL of RPMI 1640. Cell viability was evaluated with the Trypan blue exclusion test and was more than 95%. Cell preparations were adjusted to 5 x 106 cells/mL for immunocytochemistry and 106 cells/mL for chemiluminescence assays on PMNs.

Leptin receptors of PMNs were then sought through the use of affinity-purified goat polyclonal antibodies directed to the extracellular domain by immunocytochemistry. The specific IgGs were purified by human leptin receptor affinity chromatography and then biotinylated. Specificity for OB-R had been tested by immunocytochemistry and Western blotting by the manufacturer. The principle of the test consists of first fixing a specific biotinylated anti-leptin receptor on OB-R and then visualizing this complex with peroxidase coupled to chromogenic substrate (3’,3’-diaminobenzidine hydrochloride, DAB). To obtain a satisfactory immunospecificity, we saturated the nonspecific membrane sites with fetal calf serum (FCS). To eliminate the false-positive reactions, we first eliminated reactions with endogenous peroxidases by adding hydrogen peroxide, which exhausted enzymatic activities, and then blocked endogenous biotin with avidin.

This immunocytochemistry test was carried out on slides with three different assays for each blood sample (n = 6): one slide with anti-leptin receptor (slide AC+), one slide without anti-leptin receptor to eliminate false-positive reactions (slide AC-), and one slide with leptin and anti-leptin receptor to verify the specificity of anti-leptin receptor (slide leptin-AC+).

For each slide of four wells, we deposited in duplicate the pure PMNs (two wells) and the lymphocytes (two wells). After adhesion on treated cover glass (Polylabo, Strasbourg, France), immune cells (5 x 106/mL) were fixed with cold formaldehyde (2%, pH 7.4) for 20 min at 4°C, washed with Earle’s balanced salt solution (EBSS, pH 7.4), and incubated with FCS (2%, 10 min, 37°C) to saturate nonspecific sites. The cells were then washed in EBSS, and two consecutive steps carried out to reduce nonspecific background staining. First, cells were incubated with medium containing 3 mM sodium azide, 1% hydrogen peroxide, and 0.1% saponin (30 min, in the dark at room temperature) to block endogenous peroxidase activities. Second, cells were treated using the Avidin Biotin Kit for 30 min to inhibit the reaction of endogenous biotin. After washing in EBSS medium, cells were incubated with the biotinylated polyclonal anti-OB-R antibody (500 ng/mL) for 30 min. Slides were then rinsed in EBSS and incubated with the avidin-biotin-peroxidase complex (ABC method) for 30 min, washed several times in EBSS, and then incubated with peroxidase chromogen (DAB, 0.6 mg/mL with hydrogen peroxide, 0.3%, 8 min, in the dark). Slides were washed in distilled water, air-dried, counterstained with hematoxylin, cover slipped, and examined by light microscopy.

For the chemiluminescence assays (n = 7), PMNs (106/mL) were incubated (37°C, 5% CO2) with different concentrations of leptin (5, 50, 100, 250, 500, and 1,000 ng/mL) under gentle continuous agitation. In parallel, for each sample a control was set up in the same conditions except for leptin. After 180 min of incubation, oxidative species produced by stimulated PMNs were explored by chemiluminescence (luminometer 1250, LKB-Pharmacia, St. Quentin-en-Yvelines, France). Luminol (10-9 M) was introduced in the cell suspension and, after stabilization of basal chemiluminescence, stimulating agent [phorbol 12-myristate 13-acetate (PMA), 10-6 M] was added. We recorded the latent time (T1, s) corresponding to the time of initial variation of chemiluminescence after stimulation of cells by PMA and the maximum time (Tmax, s) corresponding to the time taken to reach the maximum chemiluminescence peak (mV).

Data were expressed as mean ± SEM. Statistical analysis was carried out with PCSM software (Deltasoft, Grenoble, France) and consisted of a Student’s t test between the sample receiving leptin and its corresponding control, or of an ANOVA followed by a Newman-Keuls test to compare the influence of the different concentrations of leptin on the reactive oxygen species (ROS) production. Values of P < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
As shown in Figure 1 , we detected specific OB-R on the membrane of lymphocytes (slide AC+, Fig. 1B ) as attested in the literature [16 , 18 ] compared with their control cells (slide AC-, Fig. 1A ). PMN immunostaining (Fig. 2B ) was prominent on the cellular membranes (slide AC+) compared with their controls (slide AC-, Fig. 2A ) and was characterized by a marked brown coloration on the membrane. For the control slide leptin-AC+, no coloration (Fig. 3 ) was found on the PMNs treated first with leptin and then with anti-leptin receptor, confirming the existence of a leptin receptor and attesting to the specificity of this antibody (similar pretreatment by leptin on lymphocytes yielded identical results, data not shown).



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  		Figure 1. Immunoperoxidase localization of leptin receptor on lymphocytes used as positive cell controls. Lymphocytes (5 x 106/mL) received SVF 2% only (A) or SVF 2% and specific antibody directed against OB-R (B). A) Ac- slide: no staining was observed at the cell membrane of lymphocytes. B) Ac+ slide: staining was observed at the cell membrane of lymphocytes._art>

 


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  		Figure 2. Immunoperoxidase localization of leptin receptor on PMNs. PMNs (5 x 106/mL) received SVF 2% only (A) or SVF 2% and specific antibody directed against OB-R (B). A) Ac- slide: no staining was observed at the cell membrane of PMNs. B) Ac+ slide: staining was observed at the cell membrane of PMNs._art>

 


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  		Figure 3. Existence of leptin receptor and specificity of anti-leptin receptor: leptin-Ac+ slide. PMNs (5 x 106/mL) were incubated with SVF 2% and leptin recombinant human in excess (5,000 ng/mL) before treatment by anti-leptin receptor. Leptin-Ac+ slide: no staining was observed at the PMN membrane._art>

 
Stimulation of PMNs by PMA in the presence of increasing concentrations of human recombinant leptin (5–1,000 ng/mL) led to an increase in luminol chemiluminescence at the leptin concentrations of 50, 100, 250, and 500 ng/mL (Fig. 4A ). In particular, pre-incubation of PMNs with 250 ng/mL of leptin for 180 min strongly enhanced the ROS production, which was double that of the control (Table 1 ). A correlation was also observed between variations of the chemiluminescence of the leptin sample relative to the chemiluminescence of the control and the concentration of leptin used for pre-incubation of PMNs (r2 = 0.98, P < 0.01; Fig. 4B ). No difference was observed between the T1 and the Tmax measured, whatever the concentration of leptin used for PMN pre-incubation (Table 1) .



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  		Figure 4. (A) Effect of different concentrations of leptin on accumulation of oxidative species by stimulated PMNs detected using luminol chemiluminescence. PMNs were incubated for 180 min with increasing concentrations of leptin: 5, 50, 100, 250, 500, or 1,000 ng/mL. Simultaneously, controls were set up in the same conditions for each sample. Chemiluminescence was measured at the maximal light emission and was expressed in millivolts. Results were means ± SEM of five to seven different assays. Statistical analysis was carried out using a Student’s t test between samples receiving leptin and corresponding controls. Values of P < 0.05 were considered significant. (B) Correlation obtained between variation of the chemiluminescence of leptin sample relative to the chemiluminescence of control sample (in percentage) and the concentration of leptin used (ng/mL) for pre-incubation of PMNs. Coefficient of correlation was estimated by a Pearson test with a reliance interval of 0.99.

 

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  		Table 1. Chemiluminescence Assays: Variations of oxygen species (leptin sample/control sample, in percentage) produced by stimulated PMNs in presence of different concentrations of leptin detected by luminol chemiluminescence and times related to the chemiluminescence assay.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this work we found that leptin may be able to modulate the functions of other immune cells that are important in the host defense system, namely PMNs. We first demonstrated that PMNs express OB-R. The isoform involved was not determined because the anti-leptin receptor used for immunocytochemistry specifically recognizes the extracellular part of the OB-R, which is common to the different isoforms of the receptor. This OB-R is evidently functional because we observe an effect of leptin on PMN functions. These findings suggest that the OB-R detected on PMNs may be the isoform with the longest cytoplasmic domain (OB-Rb), which is responsible for the activation of the Janus kinases/STAT pathway, and is expressed in various immune cells such as lymphocytes [18 ]. Further work is required to test this hypothesis.

We found that stimulation of human PMNs by leptin leads to an enhanced accumulation of ROS. This stimulating effect was significant for the concentrations of leptin used between 50 and 500 ng/mL with a maximal effect for the concentration of 250 ng/mL. This effect seemed nonsignificant for the concentrations of 5 ng/mL (plasma physiological concentration) and 1,000 ng/mL of leptin, probably because of the dispersion of the values observed or because of the different number of samples (n = 5–7).

In the same way, it was recently found that leptin increases the accumulation of ROS in endothelial cells [22 ]. In this study, these effects were concentration-dependent from 1 to 100 ng/mL, as we likewise observed for concentrations of 5–250 ng/mL.

In conclusion, this study is the first to show that PMNs express functional OB-R and that leptin stimulates ROS production by these immune cells. Our results strongly support the hypothesis that leptin is a cytokine-like proinflammatory agent. Further work is required to find out more about this possible role of leptin in the immune response in aggression situations.

Received March 31, 2000; revised October 8, 2000; accepted October 16, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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