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*
Department of Medicine, Laval University Heart and Lung Institute, Laval Hospital, Ste-Foy, Quebec, Canada; and
Department of Medicine, Pulmonary Research Group, University of Alberta, Edmonton, Alberta, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-nitro-L-arginine methyl
ester) before the addition of histamine abrogated the inhibitory effect
of the latter on TNF release. Histamine treatment (10-5 M)
increased the release of IL-10 from unstimulated (2.2-fold) and
LPS-stimulated (1.7-fold) AMs. Unstimulated AMs, NR8383, express few
copies of IL-10 mRNA, as tested by quantitative PCR, but expression of
IL-10 was increased by 1.5-fold with histamine treatment. Moreover, the
stimulation of IL-10 release by histamine was abrogated by pretreatment
with anti-PGE2 or the NO synthase inhibitor,
N-nitro-L-arginine methyl ester. Thus,
histamine increases the synthesis and release of IL-10 from AMs through
PGE2 and NO production. These results suggest that
histamine may play an important role in the modulation of the cytokine
network. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and TNF (11, 12, 13, 14, 15) and increase the
release of IL-5 (13), IL-6 (16), and IL-8
(17).
A panoply of cytokines and cell types are involved in the pathogenesis
of asthma. Alveolar macrophages
(AMs),3 which are
found throughout the respiratory tract and represent the most abundant
cells in the airway lumen, play a crucial role in determining the
development of immune responses, Th1/Th2, in the lung. AMs produce both
Th1 (IL-12) and Th2 (IL-10 and IL-13) cytokines (18, 19)
and secrete a panoply of mediators, including TNF, IL-1, IL-6, IL-8,
and NO (19, 20, 21, 22). TNF plays a pivotal role in inflammation
by stimulating inflammatory cells and increasing the production of
cytokines such as IL-1, IL-6, IL-8, and IL-12 (22, 23).
Furthermore, there is some evidence suggesting an important role of TNF
in the development of the Th1 response (24). Whereas TNF
is often an inflammatory cytokine, IL-10 is usually considered an
immunosuppressive and anti-inflammatory cytokine (25).
IL-10 inhibits the production of IL-1, IL-6, IL-8, IL-12, and TNF by
activated macrophages (26) as well as that of IFN- by
Th1 cells (27). Thus, AMs produce both pro- and
anti-inflammatory cytokines, which implies that a good balance in
the production of these cytokines is crucial to maintain the
homeostasis of the lung.
Histamine is released during allergic reactions and is found in bronchoalveolar lavages of asthmatic patients after allergic reactions (28). The presence of histamine in the airways may modulate cytokine production by AMs, thus affecting the inflammatory responses in the lung. Thus, we tested the hypothesis that histamine released during allergic reactions modifies cytokine production by AMs modulating the cytokine network. We investigated the effect of histamine pretreatment on the release of TNF and IL-10 by AMs stimulated with suboptimal concentrations of LPS. Here, we demonstrate that histamine inhibits the release of TNF from AMs in a dose-dependent manner by stimulating the synthesis and release of IL-10. The inhibitory effect of histamine on TNF release was mediated through H2 and H3 receptors and was modulated by the production of NO and PGE2. Furthermore, stimulation of IL-10 production by histamine was abrogated by the NO synthase inhibitor and anti-PGE2 Ab.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Outbred male Sprague Dawley rats were obtained from Charles River Canada (St. Constant, Canada) and were maintained in an isolation room with filter-topped cages to minimize unwanted infections. The animals were given food and water ad libitum and were maintained on a 12-h light, 12-h dark cycle. The experimental protocol was approved by the University of Alberta animal care committee in accordance with the guidelines of the Canadian Council on Animal Care.
Reagents
LPS from Salmonella enteritidis, histamine,
H1 receptor agonist (betahistine),
N-nitro-L-arginine
methyl ester (L-NAME), and goat anti-mouse
IL-10 Ab (IgG; bioactivity was assessed by IL-10 neutralization test in
MC/9 cells; neutralizing dose (50%), 7.8 µg/ml) were purchased from
Sigma (St. Louis, MO). The H2 receptor agonist,
dimaprit, was obtained from ICN (Aurora, OH), and the
H3 receptor agonist,
R-
-methyl-histamine, was purchased from RBI (Natick, MA).
Rabbit anti-TGF-ß neutralizing Ab (dilution of 1/50 inhibited the
effect of 10-10 M TGF-ß (29) on
mast cells) was obtained from R&D Systems (Minneapolis, MN), and Ab to
PGE2 was purchased from Biotechnology (Lake
Placid, NY). The pH of all solutions was adjusted to 7.2 before use.
RPMI 1640 medium (Life Technologies, Burlington, Canada) and PBS
contained <0.05 endotoxin unit when tested using an E-Toxate kit
(Sigma).
Cells
AMs were isolated as previously described (30). Briefly, animals were anaesthetized and exsanguinated by cutting abdominal aorta. The trachea was catheterized with a polyethylene tube, and airways were washed with 50 ml of cold PBS by repeated instillation of 8–10 ml. Cells from rat bronchoalveolar lavage contained 96.6 ± 0.5% AMs according to May-Grünwald Giemsa and nonspecific esterase staining. The viability always exceeded 95%.
The Sprague Dawley rat AM cell line (NR8383) was grown and maintained in Ham’s F-12 medium (Life Technologies, Grand Island, NY) supplemented with 1 mM glutamine, 15% FBS, and antibiotic as previously described (31).
Alveolar cells from normal nonsmoker subjects were obtained by bronchoalveolar lavages. AMs were purified by adherence on plastic for 2 h (95.5 ± 0.5% AMs) and were treated with histamine as indicated in the text.
Stimulation of cytokine release
AMs were incubated in RPMI 1640 medium for 2 h to allow
adherence, washed gently, and resuspended in fresh medium. Cells were
treated with histamine or histamine agonists for 2 h (as specified
in the test) before addition of LPS (1–5 ng/ml) for 4 h. At the
end of the treatment, cell-free supernatants were collected, and TNF
and IL-10 contents were measured using an immunoassay kit for rat TNF
and rat IL-10 (BioSource, Camarillo, CA) with a sensitivity of <5
pg/ml. MIP-1 and RANTES were also measured using an ELISA developed
in our laboratory as previously described (30).
Measurement of NO2- production.
AMs were treated with histamine for 48 h, and cell-free supernatants were assayed for NO2- using the Griess reaction. Briefly, 500 µl of supernatant was incubated with 250 µl of 1% sulfanilamide (Sigma) and 250 µl of 1% N-1-naphthylenediamine dihydrochloride (Sigma) in 5% H3PO4 at room temperature for 5 min. The NO2- concentration, proportional to OD540, was determined using a spectrophotometer (Beckman, Mississauga, Canada) with reference to a standard curve (NaNO2) with a sensitivity of 0.05 µM.
RNA isolation and RT-PCR
AMs, NR8383, were treated with or without histamine for 2 h, followed by LPS (1 ng/ml) for 3 h, and total RNA was extracted using an RNeasy minikit (Qiagen, Mississauga, Canada) according to the manufacturer’s protocols. Total RNA was quantified using RiboGreen RNA quantitation reagent (Molecular Probes, Eugene, OR), and results were read on a Fluoroskan Ascent FL (Labsystems, Franklin, MA). For cDNA synthesis, 1 µg of total RNA was reverse transcribed by Moloney murine leukemia virus RT (Life Technologies) using a Peltier Thermal Cycler 200 (MJ Research, Watertown, MA). PCR was performed using the Qiagen Taq DNA polymerase protocol. The primers used were: 1) rat ß-actin: sense primer, 5'-ATG CCA TCC TGC GTC TGG ACC TGG C-3'; and antisense primer, 5'-AGC ATT TGC GGT GCA CGA TGG C-3'; and 2) rat IL-10: 5' primer, 5'-CAC TGC TAT GTT GCC TGC TC-3'; and 3' primer, 5'-TTC ATG GCC TTG TAG ACA CC-3'. The PCR products for ß-actin and IL-10 were 607 and 286 bp, respectively. The temperature and time were 95°C for 45 s, 62°C for 45 s, and 72°C for 2 min for both ß-actin and IL-10. After a preliminary test of PCR cycle numbers, 35 cycles were used. Products were run on a 2% agarose gel and stained with ethidium bromide. The number of copies of IL-10 in the PCR reaction was quantified using a quantitative PCR detection kit for rat IL-10 (CytoXpress) from BioSource according to the manufacturer’s protocols. This assay can detect as few as 10 copies of IL-10/sample.
RNA from normal human AMs was isolated, and RT-PCR was performed as described above. The primers used were 1) human ß-actin: sense primer, 5'-GTC CTT AAT GTC ACG CAC GAT TTC-3'; and antisense primer, 5'-GTG GGG CGC CCC AGG CAC CA-3' (526 bp); and 2) human H3 receptor: sense primer, 5'-CAG CTA CGA CCG CTT CCT GTC-3'; and antisense primer, 5'-GGA GCC CTT CTT GAG TGA GC-3' (588 bp). The PCR product (390 bp) for H3 receptor was sequenced at Laval University, whereas the PCR product (588 bp) has been previously cloned (32).
Statistical analysis
ANOVA combined with Fisher’s protected least significant difference test or Student’s t test for paired data were used to compare treatments. Differences were considered significant at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have demonstrated that at least a 2-h pretreatment was needed
to modulate TNF production by mast cells (15). Thus, the
modulation of TNF release by histamine was investigated with and
without a pretreatment period and using different concentrations of
LPS. AMs from rat bronchoalveolar lavage were treated with histamine
(10-5 M) for 2 h before adding LPS (1 and 5
ng/ml) for 4 h, or histamine was added at the same time as LPS.
Histamine significantly (p < 0.005) inhibited
the release of TNF by LPS-stimulated AMs only when the cells were
pretreated with histamine for 2 h (Fig. 1
a). No significant inhibition
was observed when histamine was added at the same time as LPS. The
spontaneous release of TNF was not modulated by histamine treatment
alone (27 ± 2 pg/106 AMs without histamine
and 26 ± 4 pg/106 with histamine).
Furthermore, histamine pretreatment (2 h) significantly inhibited
(68 ± 6%; n = 4) TNF release from LPS-stimulated
AMs for 18 h (data not shown). These data were also confirmed
using human AMs from normal volunteers. Histamine pretreatment
(10-5 M for 2 h) inhibited (32 ± 3%;
n = 4) TNF release by LPS-stimulated human AMs for
4 h.
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b). These AMs produce
significantly more TNF in the presence of 1 and 5 ng/ml LPS (6.5
± 1.3 and 22 ± 5 ng, respectively) compared with freshly
isolated AMs (1.8 ± 0.1 and 5.3 ± 0.7 ng, respectively).
Histamine pretreatment (2 h) inhibited TNF release from NR8383 when
they were stimulated with a low concentration of LPS (1 ng/ml) but not
with 5 ng/ml, which stimulated NR8383 to release 4.2 times more TNF
than freshly isolated AMs. Thus, NR8383, treated with 1 ng/ml LPS, were
used to further investigate the immunomodulatory effects of
histamine. Specificity of histamine receptors on AMs
To investigate which histamine receptors were involved in the
inhibition of TNF release from AMs, cells were pretreated for 2 h
with different concentrations of histamine or H1
(betahistine)-, H2 (dimaprit)-, or
H3 (R--methyl-histamine)-specific
histamine receptor agonists before being stimulated with LPS (1 ng/ml)
for 4 h (Fig. 2A).
Dose-dependent inhibition of TNF release was observed with histamine
and H2 and H3 receptor
agonists. A significant inhibition was observed at
10-7 M histamine, but at
10-6 M for dimaprit and
R--methyl-histamine. Betahistine did not significantly
modulate the release of TNF from AMs. TNF release from human AMs was
also inhibited by treatment with H2 (22 ±
3%) and H3 (32 ± 8%), but not with
H1 (5 ± 1%), receptor agonists
(n = 4). These data suggest that histamine inhibits TNF
release from AMs through both H2 and
H3 receptors.
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B). However,
additional PCR product (390 bp) was consistently detected in different
PCR reactions with mRNA from subjects 1, 3, and 4 (Fig. 2B).
Thus, this product was sequenced and had 100% identity with a portion
of the human histamine H3 receptor. Thus, both
PCR products (390 and 588 bp) correspond to human
H3 receptors. Mechanism of histamine inhibition of TNF release from AMs
To investigate the mechanism of the inhibitory effect of histamine
on NR8383, Abs to TGF-ß (dilution 1/25), IL-10 (20 µg/ml), and
PGE2 (dilution 1/25) as well as an inhibitor of
NOS, L-NAME (1 mM), were added 5 min before histamine
(10-5 M). AMs were treated with histamine for
2 h, followed by 4-h treatment with LPS (1 ng/ml). The stimulation
of TNF release by LPS was not modified by the addition of Abs or
L-NAME. Furthermore, Ab to TGF-ß did not modulate the
inhibitory effect of histamine (Fig. 3).
However, anti-IL-10, anti-PGE2, and
L-NAME abrogated the inhibition of TNF release by
histamine, suggesting that the inhibitory effect of histamine may be
mediated by multiple mechanisms.
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To verify whether histamine can stimulate the release of IL-10,
AMs were treated with histamine for 2 h before the addition of LPS
(1 or 5 ng/ml) for 4 h, or histamine and LPS were added
concurrently. Cell-free supernatants were tested for IL-10 content.
Pretreatment of AMs with histamine significantly increased the release
of IL-10 stimulated by LPS, whereas concurrent treatment with histamine
and LPS did not significantly modify the release of IL-10 (Fig. 4). The modulation of IL-10 release by
histamine was observed only when AMs were treated with a low
concentration of LPS (1 ng/ml). Interestingly, the significant
augmentation of IL-10 release corresponded to the significant
inhibition of TNF release (Fig. 1b) from AMs.
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To determine whether IL-10 release observed in culture supernatants
reflected an increase in steady state levels of mRNA for IL-10, RNA was
isolated from sham-treated cells or from cells treated with and without
histamine (2 h) and LPS (1 ng/ml) for 3 h, and RT-PCR analysis was
performed. Unstimulated AMs expressed low amounts of IL-10 mRNA, but
histamine treatment alone stimulated the expression of IL-10 mRNA (Fig. 5A). LPS treatment increased
the expression of IL-10 mRNA, which was further increased by
pretreatment with histamine (10-5 M).
Quantification of mRNA for rat IL-10 using a quantitative PCR detection
kit showed an increase of 1.5-fold with histamine treatment alone and
of 1.2-fold in the presence of LPS (Fig. 5B).
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To verify whether NO and PGE2 were involved
in the stimulation of IL-10 release by histamine, AMs were treated with
L-NAME and anti-PGE2 before the
addition of histamine. Histamine alone significantly increased the
release of IL-10 at a level similar to LPS and further increased
LPS-stimulated IL-10 release (Fig. 6).
However, in the presence of anti-PGE2 or an
inhibitor of NO, histamine did not modify IL-10 release from AMs,
suggesting that these two mediators are involved in the
immunomodulatory effects of histamine.
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Modulation of chemokine release by histamine
To investigate the modulatory effect of histamine on chemokine
release, AMs were treated for 2 h with histamine
(10-5 M) followed by LPS (1 ng/ml) for 4–20 h.
Cell-free supernatants were tested for the presence of MIP-1 and
RANTES. LPS stimulated the release of both chemokines (3-fold), but
histamine treatment (20 h) did not modify their release (4.9 ±
0.1 ng of MIP-1 and 151.4 ± 23.5 pg of
RANTES/106 AMs without histamine and 5.0 ±
0.5 ng of MIP-1 and 157.4 ± 24.8 pg of
RANTES/106 AMs with 10-5 M
histamine).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This is the first evidence of the presence of H3
receptors on AMs. The H3 receptor agonist used in
this study (R--methyl-histamine) has a relative activity
related to histamine of 0.49, 1.02, and 1550 on
H1, H2, and
H3 receptors, respectively (35).
Thus, the high specificity of H3 receptor agonist
strongly indicates the presence of H3 receptors
on AMs. Furthermore, we demonstrated the presence of
H3 receptor mRNA in human AMs from four
volunteers. Interestingly, AMs from one subject did not show any PCR
product for H3 receptor (data not shown), whereas
three volunteers showed more than one PCR product (Fig. 2B).
The sequencing of 588-bp (32) and 390-bp PCR products
showed 100% homology with human histamine H3
receptor. This may be explained in part by H3
receptor heterogeneity (36). There is increasing evidence
suggesting the presence of H3 receptor subtypes
(37, 38), which may correspond to the additional PCR
product observed. Thus, our data suggest that histamine modulates AM
functions through both H2 and
H3 receptors. However, further investigations are
needed to identify the subtype of H3 receptor
involved.
Inhibition of TNF release by histamine has been shown in different
sources of macrophages, but not in human AMs (39). In that
study there was no histamine pretreatment before LPS stimulation, and a
higher concentration of LPS was used. Similar results were obtained in
our laboratory in these conditions. When AM stimulation is too potent,
a substantial amount of TNF is released that histamine does not
significantly inhibit (Fig. 1b). Interestingly, human AMs
release 17 times more TNF than monocytes (34
ng/106 AMs and 2 ng/106
monocytes) when stimulated with LPS (500 ng/ml), which may explain in
part the unresponsiveness of human AMs to histamine inhibition under
these conditions (39). In our study LPS (1 ng/ml)
stimulated the release of a moderate amount of TNF (0.17 ± 0.08
ng/106 cells) from human AMs, which was inhibited
by histamine treatment. Thus, when TNF release is not maximal,
histamine can modulate its production by stimulating the release of
IL-10.
IL-10 and TGF-ß are two anti-inflammatory cytokines that inhibit TNF release (25, 29). Our data showed that TGF-ß was not implicated in the inhibitory effect of histamine on AMs. However, anti-IL-10 abrogated the inhibition caused by histamine. Furthermore, we showed that histamine stimulated the release of IL-10 from AMs. However, after 18 h of treatment with LPS, histamine did not significantly increase the release of IL-10, but still inhibited TNF production. It is possible that the presence of more IL-10 in the beginning of the incubation was sufficient to further inhibit TNF production and that, with time, IL-10 production by LPS-stimulated AMs overcomes the increase by histamine. Furthermore, we cannot exclude the possibility that other mechanisms may be involved in the inhibition of TNF production by histamine after 18 h. Interestingly, the release of IL-10 seemed to be mediated through PGE2 and NO production. Although histamine is known to stimulate the release of PGE2 and NO (40, 41), the roles of these mediators in IL-10 production are not well understood. Some evidence shows that PGE2 and NO stimulate IL-10 release (42, 43, 44). Our data suggest that a small amount of NO production stimulated by histamine may increase IL-10 release. NO synthesis from L-arginine can be catalyzed by different NO synthases, a constitutive form (cNOS) and an inducible form (iNOS). These two forms of NOS can be differentiated using specific inhibitors, such as L-NAME for cNOS. Thus, given our results with L-NAME, it seems that histamine stimulates NO release through a cNOS pathway. Although AMs are well known to produce NO through iNOS, unstimulated AMs can also produce NO via cNOS (45). This may explain why histamine alone stimulated the release of NO, but did not potentiate its release when histamine-pretreated AMs were stimulated with LPS, which increases iNOS. Thus, histamine stimulates the release of PGE2 and NO, which, in turn, may stimulate the release of IL-10 that can inhibit TNF release from AMs.
In the airways, mast cells and AMs are in close proximity, and
cooperation between these two cell types may be important in diseases
such as asthma. An increased amount of histamine is found in
bronchoalveolar lavage, reaching a concentration of 2.8 ng/ml after
allergic reactions in asthmatic patients (46). Given the
dilution of bronchoalveolar lavage fluid and the proximity of mast
cells to AMs, the concentration of histamine surrounding AMs can easily
reach 10-7-10-5 M, as
studied here. Thus, histamine released by mast cells during allergic
reactions can induce inflammation and stimulate AMs to express adhesion
molecules (47) through H1 receptors.
At the same time, histamine may modulate inflammation by reducing TNF
release through H2 and H3
receptors and increasing IL-10 release. However, histamine may also
modulate the cytokine network toward a Th2 type response by stimulating
IL-10 production. Although IL-10 shows anti-inflammatory
properties, its roles in the differentiation of Th2 cells
(48) and in the inhibition of IFN- and IL-12
(49) may potentiate the Th2-type response seen in allergic
asthma. Furthermore, histamine has been shown to inhibit IFN-
production by Th0 and Th1 cells (12). Recently, Elenkov et
al. (34) showed the suppression of IL-12 and the
stimulation of IL-10 production by human peripheral blood following
histamine treatment. In their experiments, cells were pretreated for 10
min with histamine before adding LPS. They demonstrated that the
effects of histamine were mediated through H2
receptors, but not H1 or H3
receptors, and that monocytes were the source of IL-12 and IL-10. Our
study shows that histamine stimulates IL-10 production from purified
AMs at the protein and mRNA levels and that this effect was mediated
through NO and PGE2 production. Furthermore,
histamine modulates cytokine production by AMs through
H2 and H3 receptors, in
contrast to monocytes. The presence of H3
receptors on AMs may explain in part the difference in histamine
responsiveness between AMs and monocytes. Interestingly, an increase in
IL-10 production by purified mast cells was also observed after
histamine treatment (data not shown). Fig. 7 summarizes the immunomodulatory effects
of histamine on the cytokine network.
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production, which are particularly important for NK
cell and macrophage functions. Thus, although several roles of
H2 and H3 receptors have
been characterized, further investigation is needed to understand the
modulation of the immune system of the host treated with
H2 and H3 receptor
antagonists in different diseases.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Elyse Bissonnette, Institut de Cardiologie et de Pneumologie de l’Université Laval, Hôpital Laval, 2725 chemin Ste-Foy, Ste-Foy, Quebec, Canada G1V 4G5. E-mail address:
3 Abbreviations used in this paper: AM, alveolar macrophage; L-NAME, N-nitro-L-arginine methyl ester; MIP-1, macrophage inflammatory protein-1; NOS, NO synthase; cNOS, constitutive form of NOS; iNOS, inducible form of NOS.
Received for publication May 14, 1999. Accepted for publication January 5, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-) release according to the phenotype of human Th0, Th1 and Th2 clones. Clin. Exp. Immunol. 108:545.[Medline]
production by human T cell clones from the airways and blood. Am. J. Respir. Cell Mol. Biol. 18:721. via histamine H2 receptors. J. Exp. Med. 174:281. release mast cells through H2 and H3 receptors. Am. J. Respir. Cell. Mol. Biol. 14:620.[Abstract]
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potentiates the release of TNF- and MIP-1 by alveolar macrophages during allergic reactions. Am. J. Respir. Cell Mol. Biol. 20:407. production by human alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 17:218.-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041.This article has been cited by other articles:
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, p < 0.005) inhibited the
release of TNF from AMs. The results are the mean ± SEM of four
to six experiments performed in duplicate. B, Inhibition
of TNF release from the AM cell line NR8383. Cells were treated as
described in A. Histamine significantly (*,
p < 0.05) inhibited the release of TNF when NR8383
cells were pretreated for 2 h before being stimulated with LPS (1
ng/ml). The results are the mean ± SEM of six experiments
performed in duplicate.
, Increase; 
,
inhibition.