Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 2007 Nov;150(2):340–348. doi: 10.1111/j.1365-2249.2007.03492.x

Serotonin modulates the cytokine network in the lung: involvement of prostaglandin E2

G Ménard 1, V Turmel 1, E Y Bissonnette 1
PMCID: PMC2219342  PMID: 17822443

Abstract

Serotonin, well known for its role in depression, has been shown to modulate immune responses. Interestingly, the plasma level of serotonin is increased in symptomatic asthmatic patients and the use of anti-depressants, known to reduce serotonin levels, provokes a decrease in asthma symptoms and an increase in pulmonary function. Thus, we tested the hypothesis that serotonin affects alveolar macrophage (AM) cytokine production, altering the cytokine network in the lung and contributing to asthma pathogenesis. AMs were treated with different concentrations of serotonin (10-11−10-9 M) or 5-HT1 and 5-HT2 receptor agonists for 2 h prior stimulation. T helper 1 (Th1) and Th2 cytokines, prostaglandin-E2 (PGE2) and nitric oxide (NO) were measured in cell-free supernatants. Serotonin significantly inhibited the production of tumour necrosis factor (TNF) and interleukin (IL)-12, whereas IL-10, NO and PGE2 production were increased. These immunomodulatory effects of serotonin were mimicked by 5-HT2 receptor agonist but were not abrogated by 5-HT2 receptor antagonist, suggesting the implication of other 5-HT receptors. Inhibitors of cyclooxygenase and antibody to PGE2 abrogated the inhibitory and stimulatory effect of serotonin on TNF and IL-10 production, respectively, whereas NO synthase inhibitor eliminated serotonin-stimulated IL-10 increase. Furthermore, PGE2 significantly increased AM IL-10 and NO production. These results suggest that serotonin alters the cytokine network in the lung through the production of PGE2. The reduction of Th1-type cytokine by serotonin may contribute to asthma pathogenesis.

Keywords: alveolar macrophages, human, IL-10, IL-12, NO, PGE2, serotonin, TNF

Introduction

Alveolar macrophages (AMs) are found throughout the respiratory tract from the alveolus to the larynx and play a key role in the maintenance of lung immunological homeostasis [1]. AM functions are altered in asthmatic patients [2,3], and there is increasing evidence suggesting that AMs participate in the production and maintenance of airway inflammation in asthma and allergic diseases [4]. Asthmatic subjects have increased activated AMs, which correlates with asthma severity [5,6]. Furthermore, AMs play an important role in eosinophil influx, differentiation and survival by amplifying interleukin (IL)-5 production in asthmatic patients [7]. AMs also contribute to the inflammatory process by the production of various mediators, including T helper 1 (Th1) and Th2 cytokines, which may be modulated by lung microenvironment.

Serotonin is released by human mast cells and platelets following antigen challenge [8,9]. This neurotransmitter is well known for its role in depression and anxiety [10], but there is some evidence suggesting that serotonin modulates immune responses [11–16]. Low concentrations of serotonin enhance both T cell proliferation and IL-2 production in response to suboptimal concentrations of concanavalin A [11], whereas at higher concentrations serotonin inhibits mitogen-stimulated cell proliferation and IL-2 receptor expression [12]. In addition, serotonin reduces phagocytosis of murine macrophages [13] and the production of tumour necrosis factor (TNF) and interferon (IFN)-γ by human blood leucocytes [14–16]. However, the role of serotonin in asthma is still unclear. A positive correlation between serotonin concentration and asthma symptoms and a negative correlation with their pulmonary function have been demonstrated [17]. Interestingly, treatment of asthmatic patients with tianeptine, which reduces free serotonin levels in plasma, decreases clinical asthma symptoms [17]. Furthermore, corticosteroids, which are the recommended therapy in current guidelines for asthma, reduce serotonin levels [18]. Thus, although the relation between depression and asthma symptoms is still controversial [19], there is some evidence suggesting a role of serotonin in asthma pathogenesis.

Thus, given the correlation between levels of serotonin and asthma symptoms [20] and the important role of AMs in asthma pathogenesis, we tested the hypothesis that serotonin affects AM cytokine production modulating the cytokine network. We investigated the effects of serotonin pretreatment on the release of IL-10, IL-12, TNF, nitric oxide (NO) and prostaglandin-E2 (PGE2). Here, we demonstrate that serotonin inhibits the release of IL-12 and TNF in a concentration-dependent manner, whereas IL-10, NO and PGE2 production were increased. The inhibitory effect of serotonin on TNF release and its stimulatory effect on IL-10 production were mediated, at least in part, through 5-HT2 receptor and involved PGE2 production.

Methods

Cell culture

NR8383 is a rat AM cell line that is modulated in vitro as human AMs [21]. NR8383 cells were maintained in Ham's F-12 media with 10% fetal bovine serum (FBS), 1% HEPES buffer, 1% penicillin–streptomycin (Invitrogen Canada Inc., Burlington, ON, Canada) and 0·2% garamycin (Schering Canada Inc., Pointe-Claire, QC, Canada) in a humid incubator at 37°C with 5% CO2. For the treatments, cells were suspended at 106/ml in RPMI-1640 medium (Invitrogen Canada Inc.) with 5% FBS, 1% HEPES buffer and antibiotics, as mentioned above. Cell viability (93 ± 2%) was determined by Trypan blue exclusion. After 2 h adherence at 37°C, cells were washed and treated with different concentrations of freshly prepared serotonin (Sigma Chemical Co., St Louis, MO, USA) for 2 h before being stimulated with suboptimal concentration of lipopolysaccharide (LPS) (Salmonella enteritidis, 1 ng/ml; Sigma) or bacille Calmette–Guérin [BCG; Mycobacterium bovis, 2 × 106 colony-forming units (CFU)/ml; Calbiochem, San Diego, CA, USA]. Pretreatment time and stimulus concentrations were determined in preliminary experiments. At the end of the treatment, supernatants were recovered and stored at −70°C for future analysis. In some experiments, cells were pretreated with an inhibitor of inducible NO synthase (iNOS), 4H-1,3-thiazin-2-amine,5,6-dihydro-6-methyl-, monohydrochloride (AMT, 100 µM), or an inhibitor of cyclooxygenase synthase (S)-Naproxen (10 µM) or indomethacin (1 µM), or antibody against PGE2 (dilution 1/25) (Caymen Chemical, Ann Arbor, MI, USA). The serotonin receptor agonists 5-HT1A, 8-hydroxyl-2-dipropylaminotetralin (8-OH-DPAT) and 5-HT2A/C (+/–)-1-(2,5-dimethoxy-4-iodophenyl)-2-amenopropane (DOI) were purchased from Sigma.

AMs were obtained from bronchoalveolar lavage (BAL) of non-atopic normal subjects with no history of asthma or systemic diseases (methacholine PC20 > 16 mg/ml), and subjects with mild allergic asthma (methacholine PC20 < 8 mg/ml) using only inhaled β2-agonist on demand. None used inhaled or systemic corticosteroids and all subjects were non-smokers. This study was approved by the Hospital Laval Human Ethic Committee and written consent was obtained from each subject before participation. AMs were purified (95 ± 1%) by adherence on plastic for 2 h and were treated with serotonin as indicated in the text.

Enzyme-linked immunosorbent assay (ELISA)

Cell-free supernatants were tested for cytokine content using immunoassay kits for rat TNF, IL-10 (BD Biosciences, Mississauga, ON, Canada) and IL-12p70 (Biosource International, Camarillo, CA, USA) with a sensitivity of 5 pg/ml. Human TNF and IL-10 were measured using ELISA kits from BD Biosciences with a sensitivity of 4 pg/ml, whereas IL-13 ELISA was purchased from R&D Systems (Minneapolis, MN, USA).

PGE2 assay

AMs were treated with serotonin with and without LPS (10 ng/ml) for 2 h in phosphate-buffered saline (PBS). PGE2 levels were measured in cell-free supernatants using an enzyme immunoassay (EIA) kit with a sensitivity of 7 pg/ml, according to the manufacturer's protocol (Cayman Chemical, Ann Arbor, MI, USA).

Measurement of NO production

AMs were incubated with serotonin for 2 h followed by 48 h stimulation with LPS (1 ng/ml). Cell-free supernatants were assayed for NO2– content using Greiss reaction, as described previously [21]. NO2– concentration, proportional to OD540, was determined using a VersaMax kinetic microplate reader (Thermo Max, Molecular Devices, Sunnyvale, CA, USA) with reference to a standard curve (NaNO2).

Statistical analysis

Analysis of variance, combined with Scheffé's F-test or Student's t-test for paired data were used to compare treatments. Differences were considered significant when P < 0·05.

Results

Modulation of AM cytokine production by serotonin

To investigate the modulatory effect of serotonin on the balance of Th1/Th2 cytokines, the production of IL-10, a Th2 cytokine, and IL-12 and TNF, Th1 cytokines, were investigated. AMs, NR8383, were pretreated with serotonin for 2 h stimulated or not with LPS (1 ng/ml) for 20 h and IL-10 release was measured in cell-free supernatants. Serotonin (10−11, 10−10 and 10−9 M) significantly (*P < 0·05 and ‡P < 0·01) stimulated (three-, 5·5- and 10·8-fold, respectively) the spontaneous release of IL-10 (Fig. 1a). Furthermore, serotonin (10−10 and 10−9 M) significantly increased (22% and 20%, respectively) LPS-stimulated IL-10 release. However, a high serotonin concentration, 10−6 M, did not modulate IL-10 production significantly (data not shown).

Fig. 1.

Fig. 1

Open in a new tab

Stimulation of interleukin (IL)-10 and inhibition of IL-12 and tumour necrosis factor (TNF) release by serotonin. Alveolar macrophages (AMs) were treated for 2 h with different concentrations of serotonin (10−11−10−9 M) before being stimulated or not with lipopolysaccharide (LPS) for 20 h and cell-free supernatants were tested for IL-10 content (a). Serotonin significantly (*P < 0·05) stimulated the release of IL-10. AMs were treated with serotonin for 2 h, stimulated with bacille Calmette–Guérin (BCG) for 20 h or with LPS for 4 h, and IL-12 (b) and TNF (c) release were measured in cell-free supernatants, respectively. Serotonin significantly (*P < 0·05, ‡P < 0·01) inhibited the release of both IL-12 and TNF. The results are the mean ± standard error of the mean of five experiments.

LPS concentration used for IL-10 production did not stimulate AM IL-12 release. Thus, to investigate the production of IL-12, AMs were stimulated with BCG (106 CFU/ml) for 20 h after being treated with different concentrations of serotonin for 2 h. IL-12 was measured in cell-free supernatants. Unstimulated AMs produced small amounts of IL-12 (2·6 ± 0·8 pg/106 cells), but BCG significantly stimulated AM IL-12 production (39·1 ± 5·3 pg/106 cells). Serotonin (10−10 and 10−9 M) treatment significantly (‡P < 0·01) inhibited (34%) BCG-stimulated IL-12 release (Fig. 1b).

The modulation of TNF release by serotonin was investigated in unstimulated and LPS-stimulated AMs. TNF is released rapidly by AM, reaching a maximum at 4–6 h (data not shown). Thus, AMs were pretreated with different concentrations of serotonin for 2 h followed or not by LPS stimulation (1 ng/ml) for 4 h. AMs spontaneously released detectable amounts of TNF (42·2 ± 12·2 pg/106 cells). Treatment of AMs with serotonin (10−10 and 10−9 M) significantly (*P < 0·05) inhibited both spontaneous and LPS-stimulated TNF release (Fig. 1c). The maximum inhibition of both spontaneous and LPS-stimulated TNF release (75% and 29%, respectively) was observed at 10−9 M serotonin. High concentrations of serotonin (10−6 M) did not inhibit further the release of TNF (data not shown). Thus, serotonin treatment increases and inhibits, respectively, the release of Th2 and Th1 cytokines by AMs.

Specificity of serotonin receptor on AMs

To investigate the specificity of serotonin receptors involved in the increase of IL-10 production and the inhibition of TNF release, two serotonin receptor agonists were used, 5-HT1 (8-OH-DPAT) and 5-HT2 (DOI). AMs were pretreated with 10−10 M 8-OH-DPAT and DOI for 2 h, stimulated or not with LPS for 4 h and 20 h for TNF and IL-10 production, respectively. 5-HT2 receptor agonist significantly (*P < 0·05) inhibited both spontaneous and LPS-stimulated AM TNF release (Fig. 2a) and increased LPS-stimulated IL-10 production by AMs (Fig. 2b). 5-HT1 receptor agonist did not significantly modulate AM cytokine production, suggesting that the immunomodulatory effects of serotonin are mediated via the 5-HT2 receptor. However, use of the 5-HT2 receptor antagonist, ritanserin 10−9 M, did not abrogate the inhibitory effect of serotonin on AM TNF release (control 142·1 ± 8·5 pg/106 AM; serotonin 118·5 ± 9·2 pg/106 AM; serotonin + 5-HT2 receptor antagonist 108·8 ± 8·8 pg/106 AM), suggesting the implication of other 5-HT receptors.

Fig. 2.

Fig. 2

Open in a new tab

Modulation of interleukin (IL)-10 and tumour necrosis factor (TNF) production by serotonin agonists. Alveolar macrophages (AMs) were treated with 5-HT1 (8-hydroxyl-2-dipropylaminotetralin) and 5-HT2A/C (+/–)-1-(2,5-dimethoxy-4-iodophenyl)-2-amenopropane receptor agonists (10−10 M) for 2 h before being stimulated with lipopolysaccharide (LPS). 5-HT2 receptor agonist significantly (*P < 0·05) inhibited both spontaneous and LPS-stimulated TNF release (a) and increased LPS-stimulated IL-10 production (b). The results are the mean ± standard error of the mean of five to eight experiments.

Mechanism of action of serotonin

Given that 2 h of serotonin pretreatment were required to modulate AM cytokine release (data not shown), we investigated whether serotonin stimulates the release of other mediators that can modulate AM cytokine production in an autocrine manner. Thus, AMs were pretreated with nitric oxide synthase (NOS) inhibitor (AMT), cyclooxygenase inhibitor (Naproxen) or anti-PGE2 antibody for 30 min before the addition of serotonin (10−10 M). The inhibitors used did not modulate TNF and IL-10 release significantly (Sham in Fig. 3). However, naproxen and anti-PGE2 significantly abrogated the inhibitory and stimulatory effect of serotonin on TNF and IL-10 production, respectively (Fig. 3). Interestingly, AMT did not abrogate serotonin inhibition of TNF production, but it eliminated serotonin increase of IL-10 release (Fig. 3b). These data suggest that PGE2 may be involved in the modulatory effects of serotonin on TNF and IL-10 production, whereas NO may be involved in the stimulation of IL-10 production.

Fig. 3.

Fig. 3

Open in a new tab

Implication of nitric oxide (NO) and prostaglandin (PG) production in serotonin effects. Alveolar macrophages (AMs) were treated with inducible NO synthase (iNOS) inhibitor [4H-1,3-thiazin-2-amine,5,6-dihydro-6-methyl-, monohydrochloride (AMT)], cyclooxygenase inhibitor (Naproxen) or anti-PGE2 antibody (aPGE2) for 30 min before serotonin treatment (10−10 M, 2 h) and cells were stimulated with lipopolysaccharide (LPS) for the release of tumour necrosis factor (TNF) (a) and interleukin (IL)-10 (b). Naproxen and anti-PGE2 abrogated the serotonin effect (*P < 0·05) on TNF production (a), whereas all three inhibitors eliminated the immunomodulatory effect of serotonin (*P < 0·05) on IL-10 production (b). The results are the mean ± standard error of the mean of five experiments.

To examine whether serotonin can modulate NO production, AMs were treated with different concentrations of serotonin for 2 h followed by LPS stimulation for 48 h. Serotonin did not modulate the spontaneous release of NO (data not shown), but serotonin (10−10 and 10−11 M) significantly (*P < 0·05) increased (10%) LPS-stimulated NO production (Fig. 4a).

Fig. 4.

Fig. 4

Open in a new tab

Stimulation of nitric oxide (NO) and prostaglandin E2 (PGE2) production by serotonin. Alveolar macrophages (AMs) were treated for 2 h with different concentrations of serotonin (10−11−10−9 M) before being stimulated or not with lipopolysaccharide (LPS) for 48 h for the release of NO (a) and (10−10 M) during 2 h for PGE2 release (b), respectively. Serotonin significantly (*P < 0·05) increased the release of both NO and PGE2. The results are the mean ± standard error of the mean of eight experiments.

The modulation of AM PGE2 production by serotonin was also investigated. AMs were treated with serotonin in the presence or absence of LPS for 2 h and PGE2 levels were measured in cell-free supernatants. Serotonin significantly (*P < 0·05) stimulated the release of PGE2 with and without LPS (Fig. 4b).

PGE2 is well known to inhibit TNF production [22], but its effect on IL-10 production is still debated. To explore the possible role of PGE2 in the increase of IL-10 release, AMs were treated with different concentrations of PGE2 in the presence of LPS for 20 h and IL-10 levels were measured in cell-free supernatants. PGE2 significantly (*P < 0·05 and ‡P < 0·01) stimulated the release of IL-10 in a concentration-dependent manner (Fig. 5). Thus, the immunomodulatory effect of serotonin may be mediated by PGE2. Furthermore, PGE2 treatment (100 nM) increased (4·5-fold) LPS-stimulated NO production (data not shown), suggesting that the increase of NO production may also be mediated by PGE2.

Fig. 5.

Fig. 5

Open in a new tab

Increase of interleukin (IL)-10 release by prostaglandin E2 (PGE2). Alveolar macrophages (AMs) were treated for 2 h with different concentrations of PGE2 (1–1000 nM) before being stimulated with lipopolysaccharide (LPS) for 20 h. PGE2 significantly (*P < 0·05 and ‡P < 0·01) increased the release of IL-10 production by AMs. The results are the mean ± standard error of the mean of four experiments.

Effect of serotonin on human AMs

To understand the modulatory effects of serotonin on AMs, experiments were performed with the rat AM cell line to minimize the use of human subjects. However, it was important to confirm the modulatory effect of serotonin via PGE2 and NO using human AMs. Thus, AMs from normal and mild asthmatic subjects were isolated from bronchoalveolar lavages and pretreated with 10−10 M serotonin for 2 h before being stimulated or not with LPS. Serotonin significantly (*P < 0·05) inhibited spontaneous and LPS-stimulated TNF release and the presence of indomethacin, a cyclooxygenase inhibitor, abrogated this inhibition (Fig. 6a). Furthermore, LPS-stimulated IL-10 release was significantly (*P < 0·05) increased by serotonin treatment in the absence of indomethacin (Fig. 6b). However, no difference was observed between normal and asthmatic subjects.

Fig. 6.

Fig. 6

Open in a new tab

Modulation of human alveolar macrophage (AM) tumour necrosis factor (TNF) and interleukin (IL)-10 production by serotonin. TNF release (a) was significantly (*P < 0·05) inhibited by serotonin, whereas IL-10 release (b) was significantly increased (*P < 0·05). Indomethacin (Indo), a cyclooxygenase inhibitor, abrogated the effect of serotonin. The results are the mean ± standard error of the mean of six to 10 subjects.

The modulation of human AM IL-12 and IL-13 release by serotonin was also investigated. The level of IL-12 was below the detection limit of the ELISA, but the release of IL-13 was increased by serotonin treatment (control 8·7 ± 0·3 pg/106 AM; serotonin 26·7 ± 1·9 pg/106 AM). This increase was mimicked by 5-HT2 receptor agonist (24·2 ± 5·6), but 5-HT2 receptor antagonist did not abrogate the serotonin effect (25·9 ± 2·9 pg/106 AM), suggesting the implication of more than one 5-HT receptor.

Discussion

There are controversial publications on the modulation of the cytokine network by serotonin. Serotonin antagonists have been reported to inhibit the production of IL-2 and IFN-γ by memory T cells [23]. In contrast, serotonin has been shown to reduce the production of TNF and IFN-γ in human blood leucocytes [14,15] and the secretion of IL-12 and TNF in dendritic cells [24]. To our knowledge, there is no publication on the modulation of AM cytokine production by serotonin. These cells can produce both Th1 and Th2 cytokines, influencing the balance of these cytokines in the lung.

Our data show that serotonin inhibits Th1 cytokine production by AMs. Serotonin modulation is mediated, at least in part, by 5-HT2 receptor, as reported in a number of studies using monocytes [15,16,25]. In contrast, the study of Durk et al. showed that the 5-HT2 receptor had no effect on LPS-stimulated cytokine release by monocytes [26]. They demonstrated that the modulation of cytokine release is controlled by 5-HT3, 5-HT4 and 5-HT7 receptors. Given that 5-HT2 receptor antagonist did not abrogate serotonin modulatory effects in AMs, it is most probable that 5-HT3, 5-HT4, 5-HT6 and/or 5-HT7 receptors may also be involved [26,27].

There are increased levels of PGE2 in asthmatic subjects compared with normal and AMs have been identified as the main source [28]. Given that serotonin has been shown to induce cyclooxygenase-2, a key enzyme of prostanoid biosynthesis [29], we investigated the role of this pathway in the immunomodulatory effects of serotonin. Both the inhibition of Th1 cytokine and the increase of IL-10 production were mediated by the production of PGE2, a major metabolite synthesized by cyclooxygenase. Furthermore, we demonstrated that serotonin stimulated the release of PGE2 (Fig. 4b) and that anti-PGE2 antibody abrogated the effects of serotonin (Fig. 3). PGE2 is an inflammatory mediator with a Th2-driving role [30]. PGE2 has been shown to promote the production of Th2 cytokines in murine and human Th clones, increase IL-10 signalling and inhibit IL-12 production [31–33]. Our data suggest that serotonin-stimulated PGE2 inhibits TNF release and increases IL-10 production by AMs. The inhibitory effect of serotonin on monocyte TNF synthesis has been demonstrated previously [14], but the mechanism of action was not investigated. Furthermore, serotonin did not modulate IL-10 release in whole blood cells [15], showing the importance of studying AMs that are different than monocytes [34].

NOS inhibitor abrogated the serotonin effect on IL-10 production, but not on TNF, suggesting that the inhibitory effect of serotonin on TNF production was mediated by PGE2, whereas its stimulatory effect on IL-10 production was mediated by both PGE2 and NO. To understand more clearly the relation between PGE2 and NO, we demonstrated that PGE2 increases IL-10 and NO production as suggested previously [35,36]. Furthermore, the inhibition of cyclooxygenase has been shown to prevent the induction of inducible NOS in macrophages [37]. Thus, serotonin stimulates the release of PGE2 which, in turn, inhibits TNF release and increases IL-10 and NO production. Moreover, PGE2-stimulated NO may participate in the increase of IL-10 release. Figure 7 summarizes the mechanism of action of serotonin on AMs.

Fig. 7.

Fig. 7

Open in a new tab

Schematic drawing summarizing the mechanism of action of serotonin on alveolar macrophages. ↑, increase; ↓, inhibition.

Given that the rat AM cell line, NR8383, was used in this study, it was important to confirm these data using human AMs (Fig. 6). Both normal and mild asthmatic subjects were used in this study, but no significant difference was observed between the two groups. This may be explained by the characteristics of the asthmatic population studied. The subjects had mild symptoms and used only inhaled β2-agonists as needed. They had stable asthma and have not used inhaled corticosteroids. Furthermore, spontaneous and LPS-stimulated production of TNF, IL-10 and IL-13 were similar in both groups, suggesting that AMs of these asthmatic subjects were not activated. Thus, our data suggest that increased levels of serotonin may modify the Th1/Th2 cytokine ratio to favour a Th2 response. Interestingly, similar data were observed with the use of ecstasy (3,4-methylenedioxymethamphetamine), which is well known to stimulate the release of serotonin [38–40]. Ecstasy causes a decrease in the production of Th1 cytokine (IFN-γ, IL-2 and TNF) and an increase in Th2 cytokine (IL-4 and IL-10) production, showing the relevance of our in vitro data.

Although the role of IL-10 in Th2 diseases is still debated [41,42], there is compiling evidence demonstrating its involvement in asthma. IL-10 suppresses cytokine production by Th1 cells [43], enhances B cell maturation into plasma cells [44], potentiates antigen-induced histamine release by mast cells [45], reduces IL-12 production by dendritic cells and induces a polarized Th2 response [46]. Furthermore, virus-induced asthma exacerbation is characterized by increased IL-10 production [47] and anti-IL-10 treatment abrogated airway hyperresponsiveness in allergen-challenged mice [48], suggesting an important role of IL-10 in asthma. Our data also suggest the implication of IL-10 in allergic inflammation, although it may be a consequence of PGE2 production that seems to play an important role in modulating cytokine levels. Interestingly, PGE2 and IL-10 production is increased in dendritic cells of asthmatic subjects compared with normal subjects [49], supporting our data.

Stress and emotion have been associated with asthma symptoms [19], but the mechanisms are not well defined. Treatment of depressive disorders involves drugs that modulate serotonin reuptake. Both serotonin reuptake inhibitor and stimulator have been shown to have similar efficacy in the treatment of depression [50,51]. However, there is some evidence showing that tianeptine treatment, which stimulates serotonin reuptake, reduces serotonin levels and clinical asthma symptoms [17]. Although communication between the nervous and the immune systems is complex, serotonin may represent one of the mediators involved in this interaction by stimulating PGE2, IL-10, IL-13 and NO production and inhibiting TNF and IL-12 release. Thus, serotonin may participate in asthma pathogenesis by reducing Th1 cytokine production, hence amplifying Th2 inflammation. However, more investigations are needed to understand more clearly the relationship between depression and asthma symptoms.

Acknowledgments

The authors thank Dr M. Laviolette for performing human bronchoalveolar lavages and Ms L. Trépanier for recruiting volunteers. This study was supported by Quebec Lung Association and the Canadian Institutes of Health Research.

References

  • 1.Kraal G, Broug E, Thepen T, Van Iwaarden JF, Persoons JHA. The role of alveolar macrophages in pulmonary immune function. In: Lipscomb MF, Russell SW, editors. Lung macrophages and dendritic cells in health and disease. New York: Marcel Dekker Inc.; 1997. pp. 203–20. [Google Scholar]
  • 2.Burastero SE, Magnani Z, Confetti C, et al. Increased expression of the CD80 accessory molecule by alveolar macrophages in asthmatic subjects and its functional involvement in allergen presentation to autologous TH2 lymphocytes. J Allergy Clin Immunol. 1999;103:1136–42. doi: 10.1016/s0091-6749(99)70189-2. [DOI] [PubMed] [Google Scholar]
  • 3.Alexis NE, Soukup J, Nierkens S, Becker S. Association between airway hyperreactivity and bronchial macrophage dysfunction in individuals with mild asthma. Am J Physiol Lung Cell Mol Physiol. 2001;280:L369–75. doi: 10.1152/ajplung.2001.280.2.L369. [DOI] [PubMed] [Google Scholar]
  • 4.Rankin JA. The contribution of alveolar macrophages to hyperreactive airway disease. J Allergy Clin Immunol. 1989;83:722–9. doi: 10.1016/0091-6749(89)90005-5. [DOI] [PubMed] [Google Scholar]
  • 5.Cluzel M, Damon M, Chanez P, et al. Enhanced alveolar cell luminol-dependent chemiluminescence in asthma. J Allergy Clin Immunol. 1987;80:195–201. doi: 10.1016/0091-6749(87)90129-1. [DOI] [PubMed] [Google Scholar]
  • 6.Vignola AM, Chanez P, Campbell AM, et al. Airway inflammation in mild intermittent and in persistent asthma. Am J Respir Crit Care Med. 1998;157:403–9. doi: 10.1164/ajrccm.157.2.96-08040. [DOI] [PubMed] [Google Scholar]
  • 7.Tang C, Rolland JM, Li X, Ward C, Bish R, Walters EH. Alveolar macrophages from atopic asthmatics, but not atopic nonasthmatics, enhance interleukin-5 production by CD4+ T cells. Am J Respir Crit Care Med. 1998;157:1120–6. doi: 10.1164/ajrccm.157.4.9706118. [DOI] [PubMed] [Google Scholar]
  • 8.Kushnir-Sukhov NM, Brown JM, Wu Y, Kirshenbaum A, Metcalfe DD. Human mast cells are capable of serotonin synthesis and release. J Allergy Clin Immunol. 2007;119:498–9. doi: 10.1016/j.jaci.2006.09.003. [DOI] [PubMed] [Google Scholar]
  • 9.Matsuda H, Ushio H, Geba GP, Askenase PW. Human platelets can initiate T cell-dependent contact sensitivity through local serotonin release mediated by IgE antibodies. J Immunol. 1997;158:2891–7. [PubMed] [Google Scholar]
  • 10.Deakin JF. The role of serotonin in panic, anxiety and depression. Int Clin Psychopharmacol. 1998;13(Suppl. 4):S1–5. doi: 10.1097/00004850-199804004-00001. [DOI] [PubMed] [Google Scholar]
  • 11.Young MR, Kut JL, Coogan MP, Wright MA, Young ME, Matthews J. Stimulation of splenic T-lymphocyte function by endogenous serotonin and by low-dose exogenous serotonin. Immunology. 1993;80:395–400. [PMC free article] [PubMed] [Google Scholar]
  • 12.Slauson DO, Walker C, Kristensen F, Wang Y, de Weck AL. Mechanisms of serotonin-induced lymphocyte proliferation inhibition. Cell Immunol. 1984;84:240–52. doi: 10.1016/0008-8749(84)90096-0. [DOI] [PubMed] [Google Scholar]
  • 13.Sternberg EM, Wedner HJ, Leung MK, Parker CW. Effect of serotonin (5-HT) and other monoamines on murine macrophages: modulation of interferon-gamma induced phagocytosis. J Immunol. 1987;138:4360–5. [PubMed] [Google Scholar]
  • 14.Arzt E, Costas M, Finkielman S, Nahmod VE. Serotonin inhibition of tumor necrosis factor-alpha synthesis by human monocytes. Life Sci. 1991;48:2557–62. doi: 10.1016/0024-3205(91)90612-f. [DOI] [PubMed] [Google Scholar]
  • 15.Kubera M, Kenis G, Bosmans E, Scharpe S, Maes M. Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin-10. Neuropsychopharmacology. 2000;23:89–98. doi: 10.1016/S0893-133X(99)00150-5. [DOI] [PubMed] [Google Scholar]
  • 16.Cloez-Tayarani I, Petit-Bertron AF, Venters HD, Cavaillon JM. Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors. Int Immunol. 2003;15:233–40. doi: 10.1093/intimm/dxg027. [DOI] [PubMed] [Google Scholar]
  • 17.Lechin F, van der Dijs B, Orozco B, et al. Neuropharmacologic treatment of bronchial asthma with the antidepressant tianeptine: a double-blind, crossover placebo-controlled study. Clin Pharmacol Ther. 1998;64:223–32. doi: 10.1016/S0009-9236(98)90156-4. [DOI] [PubMed] [Google Scholar]
  • 18.Pretorius E. Corticosteroids, depression and the role of serotonin. Rev Neurosci. 2004;15:109–16. doi: 10.1515/revneuro.2004.15.2.109. [DOI] [PubMed] [Google Scholar]
  • 19.Janson C, Bjornsson E, Hetta J, Boman G. Anxiety and depression in relation to respiratory symptoms and asthma. Am J Respir Crit Care Med. 1994;149:930–4. doi: 10.1164/ajrccm.149.4.8143058. [DOI] [PubMed] [Google Scholar]
  • 20.Lechin F, van der Dijs B, Orozco B, Lechin M, Lechin AE. Increased levels of free serotonin in plasma of symptomatic asthmatic patients. Ann Allergy Asthma Immunol. 1996;77:245–53. doi: 10.1016/S1081-1206(10)63263-2. [DOI] [PubMed] [Google Scholar]
  • 21.Sirois J, Menard G, Moses AS, Bissonnette EY. Importance of histamine in the cytokine network in the lung through H2 and H3 receptors: stimulation of IL-10 production. J Immunol. 2000;164:2964–70. doi: 10.4049/jimmunol.164.6.2964. [DOI] [PubMed] [Google Scholar]
  • 22.Scales WE, Chensue SW, Otterness I, Kunkel SL. Regulation of monokine gene expression. prostaglandin E2 suppresses tumor necrosis factor but not interleukin-1 alpha or beta-mRNA and cell-associated bioactivity. J Leukoc Biol. 1989;45:416–21. [PubMed] [Google Scholar]
  • 23.Aune TM, Golden HW, McGrath KM. Inhibitors of serotonin synthesis and antagonists of serotonin 1A receptors inhibit T lymphocyte function in vitro and cell-mediated immunity in vivo. J Immunol. 1994;153:489–98. [PubMed] [Google Scholar]
  • 24.Idzko M, Panther E, Stratz C, et al. The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol. 2004;172:6011–19. doi: 10.4049/jimmunol.172.10.6011. [DOI] [PubMed] [Google Scholar]
  • 25.Kubera M, Maes M, Kenis G, Kim YK, Lason W. Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6. Psychiatry Res. 2005;134:251–8. doi: 10.1016/j.psychres.2004.01.014. [DOI] [PubMed] [Google Scholar]
  • 26.Durk T, Panther E, Muller T, et al. 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes. Int Immunol. 2005;17:599–606. doi: 10.1093/intimm/dxh242. [DOI] [PubMed] [Google Scholar]
  • 27.Stefulj J, Jernej B, Cicin-Sain L, Rinner I, Schauenstein K. mRNA expression of serotonin receptors in cells of the immune tissues of the rat. Brain Behav Immun. 2000;14:219–24. doi: 10.1006/brbi.1999.0579. [DOI] [PubMed] [Google Scholar]
  • 28.Profita M, Sala A, Bonanno A, et al. Increased prostaglandin E2 concentrations and cyclooxygenase-2 expression in asthmatic subjects with sputum eosinophilia. J Allergy Clin Immunol. 2003;112:709–16. doi: 10.1016/s0091-6749(03)01889-x. [DOI] [PubMed] [Google Scholar]
  • 29.Stroebel M, Goppelt-Struebe M. Signal transduction pathways responsible for serotonin-mediated prostaglandin G/H synthase expression in rat mesangial cells. J Biol Chem. 1994;269:22952–7. [PubMed] [Google Scholar]
  • 30.Shibata Y, Henriksen RA, Honda I, Nakamura RM, Myrvik QN. Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG. J Leukoc Biol. 2005;78:1281–90. doi: 10.1189/jlb.0605321. [DOI] [PubMed] [Google Scholar]
  • 31.Betz M, Fox BS. Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J Immunol. 1991;146:108–13. [PubMed] [Google Scholar]
  • 32.Snijdewint FG, Kalinski P, Wierenga EA, Bos JD, Kapsenberg ML. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol. 1993;150:5321–9. [PubMed] [Google Scholar]
  • 33.Cheon H, Rho YH, Choi SJ, et al. Prostaglandin E2 augments IL-10 signaling and function. J Immunol. 2006;177:1092–100. doi: 10.4049/jimmunol.177.2.1092. [DOI] [PubMed] [Google Scholar]
  • 34.Jin M, Opalek JM, Marsh CB, Wu HM. Proteome comparison of alveolar macrophages with monocytes reveals distinct protein characteristics. Am J Respir Cell Mol Biol. 2004;31:322–9. doi: 10.1165/rcmb.2004-0080OC. [DOI] [PubMed] [Google Scholar]
  • 35.Strassmann G, Patil-Koota V, Finkelman F, Fong M, Kambayashi T. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J Exp Med. 1994;180:2365–70. doi: 10.1084/jem.180.6.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Vivancos M, Moreno JJ. Role of Ca(2+)-independent phospholipase A(2) and cyclooxygenase/lipoxygenase pathways in the nitric oxide production by murine macrophages stimulated by lipopolysaccharides. Nitric Oxide. 2002;6:255–62. doi: 10.1006/niox.2001.0410. [DOI] [PubMed] [Google Scholar]
  • 37.Hrabak A, Vercruysse V, Kahan IL, Vray B. Indomethacin prevents the induction of inducible nitric oxide synthase in murine peritoneal macrophages and decreases their nitric oxide production. Life Sci. 2001;68:1923–30. doi: 10.1016/s0024-3205(01)00978-x. [DOI] [PubMed] [Google Scholar]
  • 38.Pacifici R, Zuccaro P, Hernandez Lopez C, et al. Acute effects of 3,4-methylenedioxymethamphetamine alone and in combination with ethanol on the immune system in humans. J Pharmacol Exp Ther. 2001;296:207–15. [PubMed] [Google Scholar]
  • 39.Connor TJ, Connelly DB, Kelly JP. Methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) suppresses antigen specific IgG2a and IFN-gamma production. Immunol Lett. 2001;78:67–73. doi: 10.1016/s0165-2478(01)00231-0. [DOI] [PubMed] [Google Scholar]
  • 40.Connor TJ. Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’): a stressor on the immune system. Immunology. 2004;111:357–67. doi: 10.1111/j.0019-2805.2004.01847.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–46. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  • 42.Hawrylowicz CM. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med. 2005;202:1459–63. doi: 10.1084/jem.20052211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989;170:2081–95. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996;97:1288–96. doi: 10.1016/s0091-6749(96)70197-5. [DOI] [PubMed] [Google Scholar]
  • 45.Lin TJ, Befus AD. Differential regulation of mast cell function by IL-10 and stem cell factor. J Immunol. 1997;159:4015–23. [PubMed] [Google Scholar]
  • 46.Buelens C, Verhasselt V, De Groote D, Thielemans K, Goldman M, Willems F. Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophage-colony-stimulating factor. Eur J Immunol. 1997;27:756–62. doi: 10.1002/eji.1830270326. [DOI] [PubMed] [Google Scholar]
  • 47.Grissell TV, Powell H, Shafren DR, et al. Interleukin-10 gene expression in acute virus-induced asthma. Am J Respir Crit Care Med. 2005;172:433–9. doi: 10.1164/rccm.200412-1621OC. [DOI] [PubMed] [Google Scholar]
  • 48.Matsumoto K, Inoue H, Tsuda M, et al. Different roles of interleukin-10 in onset and resolution of asthmatic responses in allergen-challenged mice. Respirology. 2005;10:18–26. doi: 10.1111/j.1440-1843.2005.00647.x. [DOI] [PubMed] [Google Scholar]
  • 49.Long JA, Fogel-Petrovic M, Knight DA, Thompson PJ, Upham JW. Higher prostaglandin E2 production by dendritic cells from subjects with asthma compared with normal subjects. Am J Respir Crit Care Med. 2004;170:485–91. doi: 10.1164/rccm.200311-1595OC. [DOI] [PubMed] [Google Scholar]
  • 50.Frazer A. Serotonergic and noradrenergic reuptake inhibitors: prediction of clinical effects from in vitro potencies. J Clin Psychiatry. 2001;62(Suppl. 12):16–23. [PubMed] [Google Scholar]
  • 51.Wagstaff AJ, Ormrod D, Spencer CM. Tianeptine: a review of its use in depressive disorders. CNS Drugs. 2001;15:231–59. doi: 10.2165/00023210-200115030-00006. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES