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Originally published online as doi:10.1189/jlb.0406236 on September 11, 2006

Published online before print September 11, 2006
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(Journal of Leukocyte Biology. 2006;80:1388-1394.)
© 2006 by Society for Leukocyte Biology

Effect of nicotine on IL-18-initiated immune response in human monocytes

Hideo Kohka Takahashi*, Hiromi Iwagaki{dagger}, Ryosuke Hamano{dagger}, Tadashi Yoshino{ddagger}, Noriaki Tanaka{dagger} and Masahiro Nishibori*,1

* Departments of Pharmacology,
{dagger} Gastroenterological Surgery, Transplant, and Surgical Oncology, and
{ddagger} Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

1 Correspondence: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: mbori{at}md.okayama-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nicotine is thought to inhibit the production of proinflammatory cytokines from macrophages through an anti-inflammatory pathway that is dependent on nicotinic acetylcholine receptor {alpha}7 subunit ({alpha}7-nAChR). IL-18, an important proinflammatory cytokine, is reported to induce the expression of adhesion molecules on monocytes, thus enhancing cell-to-cell interactions with T-cells and contributing to IL-18-initiated cytokine production. Accordingly, inhibition of IL-18 suppresses systemic inflammatory responses. In the present study, we found that nicotine inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes, and the production of IL-12, IFN-{gamma}, and TNF-{alpha} by PBMC. A nonselective and a selective {alpha}7-nAChR antagonist, mecamylamine, and {alpha}-bungarotoxin abolished the effects of nicotine, suggesting that this depends on {alpha}7-nAChR stimulation. It is reported that nicotine induces prostaglandinE2 (PGE2) production in PBMC through the up-regulation of cyclooxygenase (COX)-2 expression. PGE2 is known to activate the EP2/EP4-receptor, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity. Consistent with this, we found that COX-2 and PKA inhibitors prevented the effects of nicotine on adhesion molecule expression and cytokine production, indicating that the mechanism of action of nicotine may be via endogenous PGE2 production.

Key Words: prostaglandin E2 • nicotine acetylcholine receptor {alpha}7 subunit • ICAM-1 • B7 • CD40


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
IL-18 has been found to have a variety of biological actions, including stimulation of T cell proliferation, enhancement of natural killing, induction of IFN-{gamma}, and GM-CSF production by activated T-cells and promotion of Th1-type responses [1 2 3 ]. Cell-to-cell interaction between monocytes and T-cells through ICAM-1, B7, or CD40 engagement with their respective ligands play an important role in immune responses [4 5 6 ]. Recently, we found that IL-18 up-regulated the expression of ICAM-1, B7.2, and CD40 on monocytes, as well as the production of IL-12, IFN-{gamma}, and TNF-{alpha} in PBMC [7 , 8 ]. Blockade of the engagement of adhesion molecule by antibodies against ICAM-1 and B7.2 reduced the cytokine production by IL-18-treated PBMC [7 , 8 ]. This suggests that IL-18 induces cytokine production through up-regulation of adhesion molecule expression on monocytes.

Acetylcholine (ACh), a major parasympathetic neurotransmitter, effectively deactivates peripheral macrophages and inhibits the release of proinflammatory mediators. Nicotine activates nAChR, which belong to a family of ionotropic receptors consisting of five transmembrane subunits constituting ion channels. Nicotine acetylcholine receptor (nAChR) are widely distributed throughout the central and peripheral nervous system and are involved in signal transmission at the skeletal neuromuscular junction, in autonomic ganglia, and in the brain. In addition, non-neuronal cells, such as monocytes and macrophages, also express nAChR [9 , 10 ]. ACh-dependent macrophage deactivation is mediated by {alpha}7-nAChR, which is expressed in peripheral macrophages and has been described as being essential for the cholinergic anti-inflammatory pathway [9 , 10 ].

A major product of COX-initiated arachidonic acid metabolism, PGE2, which is released from antigen-presenting cells, primes naive human T-cells and enhances their production of anti-inflammatory cytokines, while inhibiting their synthesis of pro-inflammatory cytokines [11 , 12 ]. Among the four PGE2 receptor subtypes EP1, EP2, EP3, EP4, the activation of the EP2- and EP4-receptors leads to an increase in cAMP levels and PKA activity [13 , 14 ]. In a previous study, we found that PGE2 inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes, as well as the production of IL-12, IFN-{gamma}, and TNF-{alpha} by PBMC via the EP2- and EP4-receptors [7 ]. An analog of cAMP, dibutyryl cAMP mimicked the effect of PGE2 on adhesion molecule expression and cytokine production [7 ]. Nicotine is reported to induce the expression of COX-2 and the synthesis of one of its major products, PGE2, in whole blood, macrophages, and microglia through {alpha}7-nAChR stimulation [15 , 16 ]. However, the effect of nicotine-induced PGE2 production on immune cells is incompletely characterized and controversial.

In the present study, we examined the effects of nicotine on the expression of ICAM-1, B7.2, and CD40 and production of IL-12, IFN-{gamma}, and TNF-{alpha} in IL-18-treated PBMC and also investigated the involvement of PGE2 production in mediating these effects.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents and drugs
Recombinant human IL-18 was purchased from MBL (Nagoya, Japan), and nicotine (1-methyl-2-(3-pyridyl)pyrrolidine), {alpha}-bungarotoxin mecamylamine and H-89 were purchased from Sigma Chemical (St. Louis, MO). NS398 and indomethacin were from Cayman Chemical (Ann Arbor, MI). For flow cytometric analysis, FITC-conjugated mouse IgG1 mAb against ICAM-1/CD54 and PE-conjugated anti-CD14 mAb were purchased from DAKO (Glostrup, Denmark). FITC-conjugated mouse IgG1 mAb against B7.2 and CD40 from PharMingen (San Diego, CA), and FITC-conjugated an IgG1 class-matched control (CMC) was obtained from Sigma Chemical.

Isolation of PBMC and monocytes
Normal human PBMC were obtained from 10 healthy volunteers after acquiring Institutional Review Board (IRB) approval (Okayama Univ. IRB No. 106). Samples of 20 to 50 ml of peripheral blood were withdrawn from a forearm vein, after which the PBMC were prepared, and monocytes isolated from PBMC were separated by counterflow centrifugal elutriation, as described previously [7 , 8 ]. The PBMC and monocytes were then suspended at a final concentration of 1 x 106 cells/ml in the medium, as described previously [7 , 8 ].

Flow cytometric analysis for adhesion molecule expression
Changes in the expression of human leukocyte antigens, ICAM-1, B7.1, B7.2, CD40, and CD40L, on monocytes were examined by multicolor flow cytometry using a combination of anti-CD14 Ab with anti-ICAM-1, anti-B7.1, anti-B7.2, anti-CD40, or anti-CD40L Ab. PBMC at 1x106 cells/ml were incubated for 24 h. Cultured cells at 5 x 105 cells/ml were prepared for flow cytometric analysis, as described previously (7.8) and analyzed with a FACSCalibur (BD Biosciences, San José, CA). The data were processed using the CELL QUEST program.

ELISA assays
PBMC at 1 x 106 cells/ml were used for analyzing IL-12, IFN-{gamma}, TNF-{alpha} production, and monocytes at 1 x 106 cells/ml were used for analyzing PGE2 production. After culturing for 24 h at 37°C in a 5%CO2/air mixture, cell-free supernatant was assayed for IL-12, IFN-{gamma}, TNF-{alpha} and PGE2 protein by ELISA employing the multiple Abs sandwich principle (IL-12 (p70), TNF-{alpha} and IFN-{gamma} from R&D Systems, Minneapolis, MN, PGE2 from Cayman Chemical). The detection limits of the ELISA for IL-12, IFN-{gamma}, TNF-{alpha}, and PGE2 were 10 pg/ml.

Measurement of cAMP production in monocytes
Monocytes at 1 x 106 cells/ml were incubated at 37°C in a 5%CO2/air mixture. After 30 min, cells at 2 x 105 cells/200 µl/well were supplemented with TCA to a final concentration of 5% and 3-isobutyl-1-methylxanthine, an inhibitor of phosphodiesterase at 100 µM and frozen at –80°C. Frozen samples were subsequently sonicated and assayed for cAMP using a cAMP enzyme immunoassay kit (Cayman Chemical) according to the manufacturer’s instructions, for which no acetylation procedures were performed.

Statistical analysis
Statistical significances were evaluated using ANOVA followed by Dunnet’s test. A probability value of less than 0.05 was considered to indicate statistical significance. The results were expressed as means ± SEM of triplicate findings from five donors.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of nicotine on the expression of ICAM-1, B7.2, and CD40 on monocytes and the production of IL-12, TNF-{alpha}, and IFN-{gamma} by PBMC
As shown in Fig. 1 , we established the effect of nicotine on the expression of ICAM-1, B7.2 and CD40 on monocytes and its impact on the production of IL-12, TNF-{alpha} and IFN-{gamma} by PBMC. Nicotine had no effect on the expression of adhesion molecules or cytokine production in the absence of IL-18. IL-18 induced the expression of ICAM-1, B7.2 and CD40 on monocytes and the production of IL-12, TNF-{alpha}, and IFN-{gamma}, but had no effect on the expression of B7.1 and CD40L [7 , 8 ]. Nicotine inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 and production of IL-12, TNF-{alpha}, and IFN-{gamma} (Fig. 1A and 1B) . The IC50 values of nicotine for inhibition of the IL-18-enhanced ICAM-1 expression and IFN-{gamma} production were 0.8 and 1.0 µM, respectively.


Figure 1
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  		Figure 1. The effect of nicotine on the expression of ICAM-1, B7.2, and CD40 on monocytes and the production of IL-12, TNF-{alpha}, and IFN-{gamma} by PBMC. (A) The effect of nicotine at increasing concentrations from 0.1 to 100 µM in the presence (solid circles) or absence (open circles) of 100 ng/ml IL-18 on the expression of ICAM-1, B7.2, and CD40 on monocytes was determined by flow cytometry. Isotype-matched control represents FITC-conjugated IgG1. (B) IL-12, TNF-{alpha}, and IFN-{gamma} concentrations in the conditioned media were determined by ELISA. The results are expressed as the means ± SEM of triplicate findings from five donors. *P < 0.05, **P < 0.01 compared with the value for IL-18. When an error bar was within a symbol, the bar was omitted.

 
Effects of {alpha}7-nAChR antagonists on the action of nicotine
To determine the involvement of {alpha}7-nAChR in nicotine activity, we examined the effect of a nonselective {alpha}7-nAChR antagonist, mecamylamine, and a selective {alpha}7-nAChR antagonist, {alpha}-bungarotoxin, on the nicotine-induced inhibition of ICAM-1, B7.2, and CD40 expression on monocytes and production of IL-12, TNF-{alpha}, and IFN-{gamma} by PBMC in the presence of IL-18 (Fig. 2A and 2B ). The {alpha}7-nAChR antagonists reversed both the nicotine-induced inhibition of the expression of adhesion molecules on monocytes and the cytokine production by PBMC in the presence of IL-18. Mecamylamine and {alpha}-bungarotoxin both prevented nicotine inhibition of adhesion molecule expression and cytokine production but had no effects in the absence of nicotine (data not shown).


Figure 2
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  		Figure 2. The effect of nicotine acetycholine receptor {alpha}7 subunit ({alpha}7-nAChR) antagonists on the expression of ICAM-1, B7.2, and CD40 on mnocytes and the production of IL-12, TNF-{alpha}, and IFN-{gamma} by PBMC treated with nicotine. (A) The effect of a nonselective {alpha}7-nAChR antagonist, mecamylamine (solid circles) or a selective {alpha}7-nAChR antagonist, {alpha}-bungarotoxin (open circles) at increasing concentrations ranging from 0.01 to 10 nM in the presence of 100 ng/ml IL-18 and 100 µM nicotine the expression of ICAM-1, B7.2, and CD40 on monocytes was determined by flow cytometry. (B) IL-12, TNF-{alpha}, and IFN-{gamma} concentrations in the conditioned media were determined by ELISA. The results are expressed as the means ± SEM of triplicate findings from five donors. *P < 0.05, **P < 0.01 compared with the value for IL-18. When an error bar was within a symbol, the bar was omitted.

 
Effects of nicotine on the production of PGE2 in monocytes
IL-18 alone had no effect on the production of PGE2 [17 ]. As shown in Fig. 3A and 3B , nicotine induced PGE2 production in the presence or absence of IL-18 but was greater in its presence. Mecamylamine and {alpha}-bungarotoxin prevented nicotine-stimulated PGE2 production in the presence or absence of IL-18 (Fig. 3C and 3D) . Without nicotine, the {alpha}7-nAChR antagonists inhibitors had no effects on PGE2 production (data not shown). A nonselective or a selective COX-2 inhibitor, indomethacin or NS398, but not a PKA inhibitor, H-89, inhibited the nicotine-induced PGE2 production in the presence or absence of IL-18 (Fig. 3E 3F 3G) . Without nicotine, these inhibitors had no effects on PGE2 production (data not shown).


Figure 3
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  		Figure 3. The effect of nicotine on PGE2 production by monocytes. (A, B) The effect of nicotine on the concentration of PGE2 in the presence (solid circles) or absence (open circles) of 100 ng/ml IL-18 was determined by ELISA. (C, D) The effect of a nonselective or a selective {alpha}7-nAChR antagonist, mecamylamine (C) or {alpha}-bungarotoxin (D) in the presence (solid circles) or absence (open circles) of IL-18 was determined. (E–G) The effect of a nonselective or a selective COX-2 inhibitor, indomethacin (E) or NS398 (F), or a PKA inhibitor, H-89 (G), in the presence (solid circles) or absence (open circles) of IL-18 was determined. The results are expressed as the means ± SEM of triplicate findings from five donors. *P < 0.05, **P < 0.01 compared with the value for medium alone. #P < 0.05, ##P < 0.01 compared with the value for IL-18. When an error bar was within a symbol, the bar was omitted.

 
Effects of nicotine on the activation of cAMP in monocytes
Nicotine-activated intracellular cAMP in monocytes in the presence or absence of IL-18 (Fig. 4 ). The {alpha}7-nAChR antagonists, mecamylamine and {alpha}-bungarotoxin, prevented this nicotine-induced activation of cAMP in the presence or absence of IL-18. The COX-2 inhibitors, indomethacin, and NS398, also reversed the nicotine-enhanced activation of cAMP in the presence or absence of IL-18. In the absence of nicotine, {alpha}7-nAChR antagonists and COX-2 inhibitors had no effect on the activation of cAMP (data not shown).


Figure 4
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  		Figure 4. The effect of nicotine on the activation of cAMP in monocytes. (A) The kinetics of effect of 100 µM nicotine on the production of cAMP was determined by ELISA. (B) The effect of 100 µM nicotine with the {alpha}7-nAChR antagonists, mecamylamine or {alpha}-bungarotoxin, at 10 nM and the COX-2 inhibitors, indomethacin or NS398, at 100 µM in the presence or absence of 100 ng/ml IL-18 on the production of cAMP was determined. **P < 0.01 compared with the value in the absence of nicotine. ##P < 0.01 compared with the value for nicotine. The results are the means ± SEM of triplicate findings from five donors. ND, not detected.

 
The involvement of COX-2 and PKA in the action of nicotine
To investigate the involvement of COX-2 and PKA in the nicotine-induced regulation of ICAM-1, B7.2, and CD40 expression and production of IL-12, IFN-{gamma}, and TNF-{alpha}, we examined the effect of COX-2 and PKA inhibitors (Fig. 5 ). Indomethacin, NS398, and the PKA inhibitor H89 reversed the inhibitory effect of nicotine on the expression of ICAM-1, B7.2, and CD40 and the production of IL-12, TNF-{alpha}, and IFN-{gamma} in the presence of IL-18. The COX-2 and PKA inhibitors had no effect on the adhesion molecule expression and cytokine production by IL-18-treated PBMC in the absence of nicotine (data not shown).


Figure 5
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  		Figure 5. The involvement of COX-2 and PKA in nicotine activity. (A) The effect of COX-2 inhibitors, indomethacin (solid circles) or NS398 (open circles), or a PKA inhibitor, H89 (solid squares) in the presence of 100 ng/ml IL-18 and 100 µM nicotine on the expression of ICAM-1, B7.2, and CD40 on monocytes was determined by flow cytometry. (B) IL-12, TNF-{alpha}, and IFN-{gamma} concentrations in the conditioned media were determined by ELISA. The results are expressed as the means ± SEM of triplicate findings from five donors. *P < 0.05, **P < 0.01 compared with the value for IL-18 and nicotine. When an error bar was within a symbol, the bar was omitted.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Recent studies indicated that vagus nerve stimulation modulates the immune response and control inflammation through a nicotinic anti-inflammatory pathway dependent on the {alpha}7-nAChR [18 , 19 ]. This receptor is required for ACh inhibition of lipopolysaccharide-induced TNF-{alpha} production in human macrophages [9 ]. However, little is known about the effect of nicotine on adhesion molecule expression and cytokine production in IL-18-treated PBMC. As shown in Fig. 1 , we found that nicotine prevented ICAM-1, B7.2, and CD40 up-regulation by IL-18, as well as blocking the production of IL-12, TNF-{alpha}, and IFN-{gamma}. The IC50 values of nicotine for prevention of adhesion molecule up-regulation and cytokine production were within the range of concentration reported to be effective in the recent studies [9 , 10 ]. Moreover, we found that {alpha}7-nAChR antagonists reversed both the nicotine-induced inhibition of ICAM-1, B7.2, and CD40 up-regulation in monocytes and the production of IL-12, TNF-{alpha}, and IFN-{gamma} by PBMC in the presence of IL-18 (Fig. 2A and 2B) . This suggests that these effects of nicotine depend on the stimulation of {alpha}7-nAChR.

We further investigated the mechanism of action of nicotine. PGE2, which is released from antigen-presenting cells, acts on naive human T-cells to enhance their production of anti-inflammatory cytokines [11 , 12 ]. As shown in Fig. 3 A and B , we found that nicotine induced the production of PGE2 in the presence or absence of IL-18. The {alpha}7-nAChR and COX-2 inhibitors prevented nicotine-initiated PGE2 production in the presence or absence of IL-18 (Fig. 3C 3D 3E 3F) . We also determined the levels of other COX-2 metabolites, including PGE1, PGD2, PGF2, PGI2, PGJ2, and thromboxane, measured in media of monocytes treated with nicotine with or without IL-18, but all were under the level of detection (data not shown). These results suggest that the effect of nicotine on PGE2 production depends on stimulation via {alpha}7-nAChR and the expression of COX-2.

It has been reported that nicotine increases the levels of intracellular cAMP in various tissue and cells, including lung fibroblasts and pheochromocytoma cell line [20 , 21 ]. However, little is known about the involvement of endogenous PGE2 in nicotine-induced elevation of cAMP in monocytes. As shown in Fig. 4B , we found that nicotine activated intracellular cAMP in monocytes in the presence or absence of IL-18. {alpha}7-nAChR antagonists and COX-2 inhibitors prevented this nicotine-induced activation of cAMP in the presence or absence of IL-18. However, the production of PGE2 in the conditioned media was not detectable 30 min after stimulation with nicotine, while the elevation of cAMP reached the maximum level at 30 min (Figs. 3A and 4A) . A recent report suggested that PG influx into cells might be mediated by carriers such as PG transporter (PGT) [22 ], which emerges as a functional uptake-carrier with high affinity for PGE2 [23 ]. The higher uptake of PGE2 into decidual cells is likely to be mediated via PGT [24 ]. Together with these results, the endogenous PGE2 around monocytes might be efficiently removed from the conditioned media by the specific transporter. This may explain the difference in time-course change in PGE2 production and cAMP response. Further works are necessary on this line.

PGE2, a product of COX-2 initiated metabolism, is known to activate the cAMP/PKA pathway [13 , 14 ]. In a previous study, we reported that PGE2 inhibited IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes and production of IL-12, IFN-{gamma}, and TNF-{alpha} [7 ]. As shown in Fig. 5 , the COX-2 or PKA inhibitors partially reversed the inhibitory effect of nicotine on the expression of ICAM-1, B7.2, and CD40 and the production of IL-12, TNF-{alpha}, and IFN-{gamma} in the presence of IL-18. These results indicate that the additional increase in PGE2 by the combination of nicotine and IL-18 might, at least, partially account for the suppressive effect of nicotine on IL-18 enhancement of adhesion molecule expression and cytokine production (Fig. 6 ). In conclusion, we found that nicotine inhibited IL-18-elicited adhesion molecule expression and cytokine production through stimulation of {alpha}7-nAChR.


Figure 6
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  		Figure 6. The schematic of nicotine action on IL-18-induced adhesion molecule expression is shown.

 


   ACKNOWLEDGEMENTS
 
This study was supported, in part, by a grant for Promotion of Research from Okayama University (No. 21 to M. N.), a grant from Okayama Medical Foundation (to H. K. T.) and grants from Grant-in-Aid for Scientific Resarch (C) (15590467 to H. K. T. and 15590228 to M. N.).

Received April 3, 2006; revised July 17, 2006; accepted July 18, 2006.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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