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Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, FL 33612
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4 and 
2 subunits of nAChRs, but not
7 subunits, determined by RT-PCR. The nicotine treatment of MH-S
alveolar macrophages after infection with L. pneumophila
significantly enhanced the replication of bacteria in the macrophages
and selectively down-regulated the production of IL-6, IL-12, and
TNF-, but not IL-10, induced by infection. These effects were
completely blocked by a nonselective antagonist,
d-tubocurarine, for nAChRs, but not by a selective
antagonist, -bungarotoxin, for 7-nAChRs. Furthermore, the
stimulation of nAChRs with another agonist,
1,1-dimethyl-4-phenylpiperazinium iodide, showed the same effects,
which were blocked by the antagonist d-tubocurarine, on
the bacterial replication and cytokine regulation with that of
nicotine. Thus, the results revealed that nAChRs, the major exogenous
ligands of which are nicotine, are involved in the regulation of
macrophage immune function by nicotine and may contribute to the
cigarette-induced risk factors for respiratory infections in
smokers. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nicotine, a small organic alkaloid synthesized by tobacco
plants, is the addictive component of cigarette (6). The
size and lipophilic characteristics of nicotine allow for a small
amount to directly cross cell membranes, without interception by a
receptor (6), even though its primary effects are via
receptor mediation. This small alkaloid acts as an agonist at the
nicotinic acetylcholine receptors
(nAChRs)3 found mainly
in the central and peripheral nervous systems and on many other tissue
cells throughout the body, including immune cells (7, 8).
Even though the most frequent way to acquire nicotine is via cigarette
smoking and even though nAChRs are the receptor for nicotine, the
involvement of this receptor in the cigarette smoking-induced
alterations of immune cell function, particularly alveolar cells, has
not yet been well investigated. It has been briefly reported that the
effect of nicotine on airway epithelial cells triggering GM-CSF release
is via stimulation of nAChRs (9). Nicotine appears to be
one of the major immunomodulatory components of cigarettes, because it
has been shown that the treatment of human PBMC with nicotine
significantly inhibited the production of IL-2, TNF-, and IFN-
in
response to anti-CD3 stimulation (10). The suppression
of LPS-induced murine splenocyte production of IL-6, TNF-, and
IFN- by concurrent nicotine treatment has also been demonstrated
(11, 12).
The activation of macrophages to suppress bacterial growth in the cells
is an essential effector mechanism for the resolution of respiratory
infection caused by bacteria such as Legionella pneumophila
(13, 14, 15). Several cytokines such as IL-6, IL-10, IL-12,
and TNF- are produced by macrophages in response to infection and
may be involved in the regulation of bacterial growth in the cells
(16, 17, 18, 19). Thus, the modulation of production of such key
cytokines by macrophages may eventually affect the outcome of
infection. However, there has been no reported study showing how
nicotine alters the host defense of the lung, particularly immune
responses of alveolar macrophages, which are critical effector cells in
the lung defense to infection. In the present study, the mechanism of
nicotine-induced suppression of antimicrobial activity and possible
involvement of nAChRs in the modulation of immune function caused by
nicotine was examined using an in vitro L. pneumophila
infection model with MH-S alveolar macrophage cell line cells
(20).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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nAChR agonists, nicotine hydrogen bitartrate and
1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), and antagonists,
-bungarotoxin (-BGTX) and d-tubocurarine (d-TC), were
purchased from Sigma (St. Louis, MO), dissolved in pyrogen-free water,
and sterilized by filtration with a membrane. All reagents were diluted
for working concentrations with RPMI 1640 containing 10%
heat-inactivated FCS (HyClone Laboratories, Logan, UT).
Bacteria
L. pneumophila M124, serogroup 1, was originally obtained from a case of fatal legionellosis (21). The bacteria were cultured on buffered charcoal yeast extract (BCYE) medium (BD Biosciences, San Diego, CA) for 3 days at 37°C. The bacterial suspensions were prepared in pyrogen-free saline, and the concentration of bacteria was determined by spectrophotometry.
Alveolar macrophages
The MH-S murine alveolar macrophage cell line purchased from the American Type Culture Collection (Manassas, VA) was used in this study. The cells were maintained in 10% FCS-RPMI 1640. The MH-S cells were adhered to 24-well tissue culture plates at a concentration of 5x105 cells/ml for 2 h in 5% CO2 at 37°C. The resulting cell monolayers were washed with HBSS, supplied with 10% FCS-RPMI 1640 without antibiotics, and then used for experiments.
Macrophage infection
The macrophage monolayers were infected with L. pneumophila (infectivity ratio, 10 bacteria/cell) at 37°C in 5% CO2 for 30 min, washed to remove nonphagocytized bacteria, and incubated in RPMI 1640 containing 10% FCS without antibiotics. The cultures were then incubated for up to 48 h at 37°C in 5% CO2.
Macrophage treatment
The macrophage cultures infected with bacteria were treated with
varying concentrations of either nicotine (0.1–100 µg/ml) or DMPP
(0.1–100 µM) for up to 48 h at 37°C in 5%
CO2. In some experiments, macrophage cultures
infected with bacteria were pretreated with either -BGTX (100 nM) or
d-TC (10 µM) 15 min before nAChR agonist treatment; then cell
monolayers were incubated with either nicotine or DMPP for up to
48 h at 37°C in 5% CO2. The
concentrations of nAChR agonists and antagonist used were previously
confirmed to be an appropriate concentration showing stimulation and
blocking of nAChRs (22, 23, 24, 25).
Macrophage viability assay
The effect of nAChR agonists and antagonists on MH-S cell viability was determined by the viable cell number count and tetrazolium colorimetric methods. In brief, 24 h after treatment of macrophages with agonists or antagonist, the cells were washed with HBSS and then detached with trypsin-EDTA (Sigma). The cells were resuspended with RPMI 1640 containing 10% FCS and pipetted to homogenize the cell suspensions. The number of viable cells was determined with 2% trypan blue in a hemocytometer. For the tetrazolium colorimetric assay, the cells were incubated with a tetrazolium compound provided in the assay kit (CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay; Promega, Madison, WI) in accordance with the manufacturer’s manual.
Viable bacteria in cell cultures (CFU assay)
The number of viable bacteria (CFU) in cell lysates was determined by standard plate counts on BCYE medium, as described previously (26). After incubation, the cell monolayers were lysed with 0.1% saponin, and the number of viable bacteria in the lysates was determined.
Antimicrobial activity
To evaluate direct in vitro anti-L. pneumophila activity of nicotine, a culture of L. pneumophila in bacterial medium with nicotine was performed. In brief, ACE yeast extract broth medium (27) with or without varying concentrations of nicotine was dispensed to culture flasks and then inoculated with L. pneumophila at the final concentration of 5 x 103 bacteria/ml. After incubation for 24 or 48 h at 37°C, the number of viable bacteria (CFU) in the culture broth was determined by standard plate counts on BCYE medium.
ELISA
The amount of IL-6, IL-10, IL-12 p40/p70, and TNF- protein in
the culture supernatants of macrophage cultures was determined by
sandwich ELISA using matched Ab pairs and protein standard for ELISA
(BD PharMingen, San Diego, CA; IL-6, IL-10, IL-12 p40/p70) and Duoset
ELISA development system (R&D Systems, Minneapolis, MN; TNF-).
Concentrations were calculated from the standard curve performed for
each cytokine protein.
RT-PCR
Total RNA was extracted from cells by the microspin technique
with RNeasy Mini Kit (Qiagen, Valencia, CA) in accordance with the
manufacturer’s manual. Reverse transcription (RT) of total RNA (1
µg) was performed with avian myeloblastosis virus transcriptase in a
commercial reaction mixture (Reverse Transcription System; Promega).
The resulting cDNA was subjected to PCR with primers for nAChR 4,
7, and 2 subunits. The primers used were designed from GenBank
cDNA sequences using a website program, Primer 3
(http://www.path.cam.ac.uk/cgi-bin/primer3.cgi). The sequences of
primer for nAChR 4 were 5'-ATC CTG ACA TCA CCT ACG CC-3' (sense) and
5'-GGT GGT GTA CAT TGA GCA CG-3' (antisense). The sequences of primer
for nAChR 7 were 5'-CAT TCC ACA CCA ACG TCT TG-3' (sense) and 5'-TGA
GCA CAC AAG GAA TGA GC-3' (antisense). The sequences of primer for
nAChR 2 were 5'-TGT ATT TCT GTG CTG CTG GC-3' (sense) and 5'-CAC GCT
AGT GAC GAT GGA GA-3' (antisense). The PCR was performed in a
Minicycler (MJ Research, Watertown, MS) for 40 cycles, 57°C annealing
temperature. PCR products were analyzed on an ethidium bromide-stained
2% agarose gel. The specificity of PCR was confirmed by
oligonucleotide sequencing of PCR products (MWG, High Point,
NC).
Statistical analysis
Statistical analysis was performed with a paired Student t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the toxicity of both nAChR agonists and antagonists
on macrophages, the cells were incubated with various concentrations of
either nAChR agonists (nicotine, 0.1–100 µg/ml; DMPP, 0.1–100 µM)
or antagonists (-BGTX, 1–100 nM; d-TC, 0.1–10 µM) for 24 h,
and then the viability of macrophages was assessed by trypan blue dye
exclusion and tetrazolium colorimetric assay. Nicotine did not show any
cytotoxicity for the macrophages up to 10 µg/ml. However, 100 µg/ml
nicotine treatment significantly reduced the macrophage viability
(
70% reduction of viability compared with nontreated control
group). In contrast, all concentrations of DMPP, -BGTX, and d-TC
tested did not affect the cell viability. These results were consistent
in the two assay methods (data not shown).
Effect of nicotine on L. pneumophila growth
Because the growth of L. pneumophila in macrophages is
dependent on the host’s macrophage activity, treatment of macrophages
with nicotine may alter the growth of L. pneumophila in
cells if nicotine has any immunomodulatory activity on macrophages.
From the previous results, we used the concentration range of 0.1–10
µg nicotine/ml to evaluate the effect of nicotine on L.
pneumophila growth in macrophages. As shown in Fig. 1
, the treatment of macrophages with
nicotine after infection with bacteria induced an enhancement of the
growth of L. pneumophila in the cells in a dose-dependent
manner at both 24 and 48 h after infection. A significant
enhancement of L. pneumophila growth by nicotine occurred
even with a concentration as low as 0.1 µg/ml at 48 h after
infection. In contrast, it has been reported that nicotine has a direct
antimicrobial activity against some bacterial and fungal pathogens
(28). Therefore, to determine whether nicotine has a
direct modulatory activity on L. pneumophila growth, the
growth of L. pneumophila in liquid bacterial medium without
host cells in the presence or absence of nicotine (0.1–100 µg/ml)
was examined. However, nicotine did not alter the L.
pneumophila growth in the bacterial medium regardless of the
concentrations tested (data not shown). These results indicate that
nicotine does not have a direct modulatory activity on L.
pneumophila growth at the concentrations tested.
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Because nicotine enhanced the growth of L. pneumophila
in macrophages without a direct effect on bacteria, it seemed likely
that host cell modulation may be involved in the enhancement of
L. pneumophila growth by nicotine. To examine such a
possibility, the effect of nicotine on the production of macrophage
cytokines, which are known to be involved in the regulation of
bacterial growth in cells (29), was examined. As evident
in Fig. 2, the treatment of macrophages
with nicotine alone slightly induced macrophage IL-6, IL-10, IL-12, and
TNF- protein production, but this was minimal when compared with
L. pneumophila-infected macrophages. In contrast, nicotine
treatment markedly down-regulated the production of IL-6, IL-12, and
TNF- induced by L. pneumophila infection in a
dose-dependent manner, even with a concentration as low as 0.1 µg/ml
in the case of TNF-. In contrast, the production of IL-10 induced by
L. pneumophila infection was not affected by nicotine, even
with a concentration as high as 10 µg/ml. These results indicate that
nicotine may selectively alter the cytokine responses of macrophages
against L. pneumophila infection and lead to an enhancement
of bacteria growth in macrophages.
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It is widely accepted that nAChRs form a family of receptors and
that they are differentially expressed in many tissues
(30). Although the most frequent way to acquire nicotine
is via tobacco smoking, the existence of nAChRs on lung tissues and
cells has not yet been well investigated. If nAChRs exists on alveolar
macrophages, the nicotine-induced immunomodulation of macrophages may
be possibly mediated by nAChRs. To determine such a possibility, steady
state levels of nAChR mRNA (4, 7, and 2 subunits) in MH-S
alveolar macrophages were analyzed by RT-PCR. The PCR products of MH-S
cells without RT were examined as a negative control. As seen in Fig. 3, mRNAs for the nAChR 4 and 2
subunits were detected in MH-S alveolar macrophages. However, it is not
clear whether MH-S cells possibly may not express nAChR 7 because
the RT-PCR specific for 7 did not successfully demonstrate the
message (data not shown). The oligonucleotide sequencing analysis of
PCR products confirmed the specificity of both 4 and 2 (data not
shown).
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Because nicotine exerts its effects by both receptor-mediated and
non-receptor-mediated mechanisms (6), a possible
involvement of nAChRs in nicotine-induced suppression of antimicrobial
activity was examined using nAChR-specific antagonists. Macrophage
monolayers infected with bacteria were pretreated with either -BGTX
(selective antagonists for 7-nAChR) or d-TC (nonselective
antagonists for nAChRs), and then the cells were incubated with
nicotine for up to 48 h. As shown in Table I, pretreatment of macrophages with d-TC
markedly abolished the nicotine-induced enhancement of bacterial growth
at both 24 and 48 h after infection. In contrast, -BGTX
pretreatment did not significantly alter the growth of L.
pneumophila enhanced by nicotine. The treatment of nAChR
antagonists alone did not show any alteration of the bacterial growth
in the macrophages.
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When macrophages infected with bacteria were pretreated with d-TC,
nicotine-induced suppression of IL-6, IL-12, and TNF- production was
readily restored to the control levels without the modulation of IL-10
production (Fig. 4). In contrast,
pretreatment of macrophages with -BGTX did not result in recovery of
the nicotine-suppressed cytokine production. The treatment of nAChR
antagonists alone did not alter the production of cytokines tested.
Thus, the results with the nAChR antagonist treatment clearly indicate
that the nicotine-induced suppression of alveolar macrophage activity,
which is involved not only in antimicrobial activity but also cytokine
responses against bacteria, is mediated, at least, by 42-nAChRs.
The failure of blocking with the 7-nAChR antagonist -BGTX on
nicotine-induced modulation of macrophage cytokine production as well
as antimicrobial activity was consistent with the results of no
7-nAChR message expression determined by RT-PCR.
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To determine whether stimulation of nAChRs with other agonists
causes modulation of macrophage function, the effect of another nAChR
agonist on antimicrobial activity and immune responses of alveolar
macrophages was examined. The nonselective nAChR agonist DMPP was used
for this purpose. When macrophages infected with the bacteria were
treated with DMPP, a marked enhancement of bacterial growth in the
cells was observed at 24 h after infection (Fig. 5), similar to the case with nicotine.
Pretreatment of macrophages with antagonist d-TC completely abolished
the effect of DMPP. A similar effect of DMPP and blocking with d-TC on
cytokine production of the macrophages in response to bacterial
infection was also evident (Fig. 6); i.e,
the DMPP-treatment significantly down-regulated the production of IL-6,
IL-12, and TNF- induced by L. pneumophila infection. This
selective inhibition on cytokine production by DMPP was completely
blocked by d-TC treatment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.91 mg/cigarette (36), may be higher than the plasma
level. Nevertheless, the findings constitute the first in vitro
demonstration of how cigarette smoke components may contribute to risk
factors for respiratory infections in smokers. In particular, the
findings of the selective inhibition of cytokine productions, such as
IL-6, IL-12, and TNF-, by nicotine indicates how such
immunomodulation may contribute to the susceptibility of cells to
infections. TNF- is required for the prompt resolution of pneumonic
legionellosis and points to a direct role for TNF- in the activation
of phagocytes (19). The precise mechanism of
nicotine-induced suppression of antimicrobial activity of macrophages
is still unclear. However, our recent studies have shown that
epigallocatechin gallate, the major form of tea catechins, restores
nicotine-suppressed TNF- production as well as antimicrobial
activity of macrophages (our unpublished data). Therefore, it
seems likely that the impaired TNF- production may be one of the
major mechanisms responsible for the nicotine-induced impairment of
antimicrobial activity against L. pneumophila infection.
This hypothesis can be supported by previous reports that TNF- is a
strong activator for macrophages to induce anti-L.
pneumophila activity (19, 37). In contrast, the role
of the reduced IL-6 production in the nicotine-induced impaired
antimicrobial activity is not clear. However, this may not have a
direct role because of the absence of IL-6 modulatory effects on
macrophages regarding anti-L. pneumophila activity
(38).
IL-10 and IL-12 are key cytokines in the regulation of development of
Th1/Th2 responses (18, 39, 40). Therefore, the
participation of these two cytokines in the defense against L.
pneumophila infection is critical (13, 17). The
direct involvement of these cytokines in the regulation of bacterial
growth in cells is less likely. Nevertheless, the suppression of IL-12
production, but not IL-10, by nicotine may cause an alteration of Th1
development by nicotine during infection, if this occurs in vivo. In
this regard, it has been reported that the nicotine-derived
N-nitrosamine directly modulates cytokine production,
including inhibition of IL-2, IL-6, IL-10, GM-CSF, and monocyte
chemoattractant protein-1 production in the U937 human macrophage cell
line (41). It is also known that nicotine itself
suppresses in vitro production of IL-2, TNF-, and IFN- from human
PBMC (10). Therefore, the present results are consistent
with these previous reports regarding the inhibitory activity of
nicotine and its derivative on cytokine production.
nAChRs form a family of receptors that are differentially expressed
mainly in the central and peripheral nervous system, as well as on many
other tissue cells. For instance, nAChRs are found in cochlea
(8), ganglionic tissue (42), developing
muscles (43), and lymphocytes and polymorphonuclear cells
in the peripheral blood (7, 44). Although the function of
peripheral nAChRs has not been well investigated, such localization
suggests that peripheral nAChRs have nonsynaptic roles. The results of
this study clearly support a possible nonsynaptic role of nAChRs in
alveolar macrophages. Whether in muscle or neurons, nAChRs are
allosteric membrane proteins that are assembled from five subunits
according to defined combination rules. In mammals, nine homologous
subunits (2–7 and 2–4) have been identified thus far in
the nervous system whereas the 9 subunit is present in sensory end
organs (30). Equilibrium binding studies have
distinguished two main categories of nAChR pentamers on the basis of
their high affinity for either nicotine or -BGTX. The former are
considered to be formed by 4 and 2 subunits containing nAChRs,
and the latter are thought to be 7 subunit containing nAChRs
(45, 46). Furthermore, 7-nAChRs exhibit low affinity
for acetylcholine and nicotine and are rapidly desensitized, whereas
42-nAChRs are considered to form a high affinity receptor for
acetylcholine and nicotine and are desensitized slowly
(30). Although we attempted to determine the partial nAChR
subunit mRNA expression in alveolar macrophages, the results of nAChR
antagonist and agonist treatment and the determination of mRNA
expression for nAChR 4 and 2 subunits in alveolar macrophages
revealed the involvement of nAChR-mediated mechanism in the
nicotine-induced suppression of antimicrobial activity and immune
responses of macrophages. In addition, the results of this study
indicated that nicotine-induced suppression of alveolar macrophage
activity, which is involved in not only antimicrobial activity but also
cytokine responses against bacteria, is mediated, at least, by
42-nAChRs.
Thus, the present study revealed that nicotine causes an alteration of immune responses of alveolar macrophages to bacterial infection by an nAChR-mediated mechanism.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yoshimasa Yamamoto, Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612. E-mail address: yyamamot{at}hsc.usf.edu
3 Abbreviations used in this paper: nAChRs, nicotinic acetylcholine receptors; -BGTX, -bungarotoxin; AYE, ace yeast extract; BCYE, buffered charcoal yeast extract; DMPP, 1,1-dimethyl-4-phenylpiperazinium iodide; d-TC, d-tubocurarine; RT, reverse transcription.
Received for publication July 24, 2001. Accepted for publication October 3, 2001.
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 K. Matsunaga, T. W. Klein, H. Friedman, and Y. Yamamoto Epigallocatechin Gallate, a Potential Immunomodulatory Agent of Tea Components, Diminishes Cigarette Smoke Condensate-Induced Suppression of Anti-Legionella pneumophila Activity and Cytokine Responses of Alveolar Macrophages Clin. Vaccine Immunol., July 1, 2002; 9(4): 864 - 871. [Abstract] [Full Text] [PDF]
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, 24 h after infection; 
, 48 h
after infection. Data represent the means + SD of relative bacterial
growth to control for triplicate macrophage cultures. Data are
representative of three experiments. *, p <
0.05, significantly different from the nicotine-untreated control group
at the same time point. The numbers of viable bacteria (CFU) of the
control group 24 and 48 h after infection were 2.6 ±
1.4 x 105 and 1.2 ± 0.4 x
106, respectively.
