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J Dent Res 84(11):999-1004, 2005
© 2005 International and American Associations for Dental Research

RESEARCH REPORT
Biological

VIP Inhibits Porphyromonas gingivalis LPS-induced Immune Responses in Human Monocytes

N. Foster*, J. Cheetham, J.J. Taylor, and P.M. Preshaw

Oral Microbiology and Host Responses Group, School of Dental Sciences, University of Newcastle Upon Tyne, NE2 4BW, UK;

* corresponding author, neil.foster{at}ncl.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lipopolysaccharide (LPS) from the Gram-negative pathogen Porphyromonas gingivalis (Pg) stimulates cytokine secretion in immune cells, and thereby initiates the inflammation associated with periodontitis. Modulation of pro-inflammatory cytokine activity is a plausible therapeutic target in periodontal disease. Vasoactive intestinal peptide (VIP) has a role in immunoregulation, and has been identified as a molecule with therapeutically beneficial immunosuppressive effects in inflammatory and autoimmune conditions. We aimed to investigate the effect of VIP on immune responses induced by Pg LPS in vitro. VIP (10–8 M) significantly (P < 0.05) inhibits TNF-{alpha} production by human monocytic THP1 cells stimulated with Pg LPS. In parallel, we showed that VIP inhibits nuclear translocation of NF{kappa}B and c-Jun in a time-dependent manner, but does not decrease the expression of CD14 receptors. This is the first report to show the potential of VIP as an immunomodulator of Pg-stimulated inflammatory pathways in human monocytes.

KEY WORDS: monocyte • VIP • Porphyromonas gingivalis • LPS


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Vasoactive intestinal peptide (VIP) is produced by both myeloid and lymphoid cells (Leceta et al., 1996; Ganea et al., 2003), and has been shown to inhibit the production of inflammatory cytokines, including TNF-{alpha} and IL-12, from murine macrophages stimulated with LPS from the enteropathogen Escherichia coli (Xin and Sriram, 1998; Delgado et al., 1999c). In murine models of E. coli-induced sepsis, VIP has been shown to rescue mice from lethal disease by decreasing the levels of TNF-{alpha} and IL-6 in blood (Delgado et al., 1999d), while increasing production of anti-inflammatory IL-10 (Delgado et al., 1999b). We have also shown that VIP inhibits TNF-{alpha} and IL-1ß production in murine macrophages infected with virulent Salmonella typhimurium, even in the presence of IFN-{gamma} (Foster et al., 2005), which potentiates immune responses in these cells (Foster et al., 2003), thus suggesting that VIP has great potential in the treatment of inflammatory pathologies.

VIP has been reported to be present in gingival crevicular fluid (GCF) in patients with chronic periodontitis (Linden et al., 2002), and this study remains one of the few studies to show active VIP production during inflammatory disease in humans. Porphyromonas gingivalis (Pg) is a key pathogen that is strongly implicated in the pathogenesis of periodontal disease (Lamont and Jenkinson, 1998). However, Pg LPS is structurally different from enteropathogenic Gram-negative bacteria (Ogawa, 1993), and many immunological studies have reported that different immune responses are induced by Pg compared with LPS from E. coli (Dixon et al., 2004). For example, whereas intravenous or intra-peritoneal injection of Pg LPS induces higher secretion of anti-inflammatory cytokines than pro-inflammatory cytokines from the lymph nodes and splenocytes of mice, the opposite effect is measured when E. coli LPS is used (Pulendran et al., 2001). Furthermore, when human monocyte-derived dendritic cells (MDDC) are stimulated with LPS from Pg or E. coli, they have different effects on T-cell populations: Pg-stimulated MDDC elicit Th2 responses, and E. coli-stimulated MDDC elicit Th1 responses (Jotwani et al., 2003). At the molecular level, E. coli LPS signals immune responses in myeloid cells by binding to Toll-like receptor 4 (TLR4), whereas there is substantial evidence that Pg LPS utilizes TLR4 as well as TLR2 (Darveau et al., 2004; Zhou et al., 2005). The aim of this research was, therefore, to assess the effect of VIP in modulating immune responses produced by human monocytes in response to Pg LPS.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
THP1 Monocyte Cell Culture
Human pro-monocytic THP1 cells were purchased from the European Collection of Cell Cultures (Salisbury, UK). Cells were cultured in RPMI media (Sigma, Poole, UK) supplemented with fetal calf serum (10%v/v), L-glutamine (2 mM), penicillin (100 U/mL), streptomycin (100 µg/mL), and amphotericin-B (2.5 µg/mL) and maintained at 37°C and 5% CO2. Prior to use, 5 x 105 THP1 cells per well were differentiated to monocytes in 24-well tissue culture plates (Greiner Bio-one Ltd, Stonehouse, UK), with 0.1 µM 1,25 dihydroxyvitamin D3 (VitD3) (Merck Biosciences, Nottingham, UK) for 24 hrs, as previously reported (Kitchens et al., 1992). Differentiation of THP1 pro-monocytes into THP1 monocytes was confirmed by increased expression of CD14 in monocytes, as determined by flow cytometry (see below) (Fig. 1Go). During cell culture, viability was assessed by Trypan blue exclusion and cell numbers monitored by a hemocytometer. LPS from Pg strain W50 (a gift from Dr. M. Rangarajan, QMW College, School of Medicine and Dentistry, London, UK) was used to stimulate THP1 monocytes for 6 or 24 hrs in the presence or absence of VIP. Unless otherwise indicated, all reagents were purchased from Sigma (Poole, UK).



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  		Figure 1. CD14 expression and flow cytometric analysis of VitD3-treated THP1 cells. (A) FACS analysis of CD14 expression on THP1 surface; arrows show CD14 expression on the surfaces of pro-monocytic THP1 cells and VitD3-treated monocytic THP1, compared with an isotype control. The histogram is representative of results repeated on at least 5 separate occasions. (B) Population of cells gated prior to FACS analysis (R1) with characteristics of high forward scatter (FSC) (largest cells in population) and low (< 102) side-scatter (non-granular cells).

 
Flow Cytometry for CD14 Expression
CD14 expression was analyzed in THP1 monocytes by flow cytometry. At least 1 x 106 cells per group were centrifuged at 300 g for 10 min in a Sigma 3K10 centrifuge (SLS, Nottingham, UK). The cells were then washed 3 times in FACS buffer (PBS containing 1% w/v BSA, 0.05% w/v NaN3). To block FC receptor activity, cells were incubated with mixing in PBS containing human serum (10% v/v) for 15 min at room temperature. Blocked cells were washed 3 times in ice-cold FACS buffer before being incubated with anti-human CD14 conjugated to phycoerethryn (PE) (1/10 in FACS buffer) (Serotec, Oxford, UK) for 45 min in darkness and on ice on a Rotatest end-to-end shaker (Luckham, Burgess Hill, UK). The cells were then washed 3 times in ice-cold FACS buffer and re-suspended in 300 µL FACS buffer prior to analysis.

All analyses were performed on a FacScan analyzer (Becton Dickinson, San Jose, CA, USA), and all cell populations were gated on high forward-scatter for further assurance of monocytic characteristics. 1 x 104 cells were analyzed in each treatment, and all treatments were compared with an isotype control murine IgG2a conjugated to PE (1/10 in FACS buffer) (Serotec). FACS data were analyzed by WinMDI version 2.8.

TNF-{alpha} ELISA
TNF-{alpha} was used as a reporter of LPS stimulation and VIP inhibition and was measured in cell supernatants with the use of a commercially available ELISA kit (DuoSet, R&D Systems, Abingdon, Oxford, UK). To determine the optimum Pg LPS concentration for stimulation experiments, we incubated THP1 cells for 6 or 24 hrs at 37°C and 5% CO2, with LPS concentrations ranging from 1 ng/mL to 10 µg/mL prior to measurement of TNF-{alpha} concentrations in cell supernatants. Subsequently, cells were incubated with 100 ng/mL LPS and co-cultured with VIP concentrations between 10–6 and 10–10 M, so that the effect of VIP on LPS-stimulated TNF-{alpha} production could be determined.

Localization of NF{kappa}B and c-Jun by confocal laser scanning microscopy
Following experimental treatments, adherent cells were permeabilized in 0.5% (v/v) Triton-X 100 for 10 min at room temperature. The cells were then washed 3 times in PBS containing 0.05% (w/v) Tween 20 (PBS-Tween). Cells were incubated for 60 min with either PBS-diluted mouse anti-human NF{kappa}B, 5 µg/mL, or mouse anti-human c-Jun, 5 µg/mL (Autogen Bioclear, Calne, UK). Following incubation, the cells were washed 3 times in PBS-Tween, and vacant binding sites were blocked for 60 min by PBS-Tween and BSA (1% w/v). After being washed a further 3 times, the cells were incubated with anti-mouse IgG conjugated to FITC, 5 µg/mL, or anti-mouse IgG conjugated to Alexa 546, 5 µg/mL (Molecular Probes, Paisley, UK), for 45 min at room temperature in darkness. After the cells were washed 3 times, their nuclei were counter-stained with 4', 6', Diamidino-2-phenylindole (DAPI), 10 µg/mL. Cells were analyzed under a TCS SP2 UV confocal laser scanning microscope (Leica, Heidelberg, Germany). In all cases, Z plane sections were analyzed by Leica software, and images shown were recorded at the level of the cell nucleus. Results were verified by an independent expert observer.

Statistical Analysis
We used the Student’s t test to identify whether significant differences existed between two specified means (LPS-cultured cells and cells co-cultured with both LPS and VIP). Significance was determined at p < 0.05 (5% confidence limit).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Conversion of Pro-monocytic THP1 Cells to Mature Monocytes
Differentiation of pro-monocytic THP1 cells into mature monocytic cells by VitD3 treatment was confirmed by greater expression of CD14 on the surfaces of adherent cells compared with that of non-adherent pro-monocytes which were not cultured with VitD3 (Fig. 1AGo). For further FACS analyses, mature monocytes were selected by gating on the basis of low side-scatter (non-granular cells) and high forward-scatter (largest cells in population), for further assurance that these cells had monocytic characteristics (Fig. 1BGo).

VIP Inhibits Pg LPS-induced TNF-{alpha} Secretion in THP1 Monocytes
We examined the effect of Pg LPS and/or VIP on TNF-{alpha} production in THP1 monocytes. Pg LPS potently induced TNF-{alpha} production from monocytes at low concentration (1 ng/mL), with maximal TNF-{alpha} being observed at an LPS concentration of 1000 ng/mL (Fig. 2AGo). However, an LPS concentration of 100 ng/mL very effectively stimulated TNF-{alpha} and was used in all further experiments. Co-culture of monocytes with LPS 100 ng/mL and VIP 10–8 M significantly (p < 0.05) inhibited TNF-{alpha} production (Fig. 2BGo). This effect was not due to differential cell survival rates following different treatments, since THP1 viability remained high in all cultures (> 85%), even after 24 hrs (data not shown).



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  		Figure 2. TNF-{alpha} production by THP1 monocytes. (A) Cells were incubated in medium alone or stimulated with increasing concentrations of Pg LPS for 6 and 24 hrs. All treatments induced significant increases (P < 0.05) in TNF-{alpha} production compared with that in unstimulated (control) cells. (B) LPS (100 ng/mL)-stimulated cells incubated with and without VIP (10–8 M). TNF-{alpha} levels were measured by ELISA and compared with unstimulated (control) cells or cells stimulated with phorbol myristate acetate (positive control). Data are presented as means ± SD (n = 3). *P < 0.05. Similar data were obtained from 3 separate experiments.

 
VIP Inhibits Nuclear Translocation of NF{kappa}B and c-Jun in LPS-stimulated THP1 Monocytes
The cellular locations of the transcription factors NF{kappa}B and c-Jun, which are critical for TNF-{alpha} gene activation, were examined in LPS-stimulated THP1 monocytes cultured with and without VIP. In unstimulated cells, NF{kappa}B and c-Jun were located in the cytoplasm of the monocytes (Figs. 3AGo, 3DGo, respectively). NF{kappa}B and c-Jun activities were temporally separated, such that 100 ng/mL LPS induced early (within 90 min) nuclear translocation of NF{kappa}B (Fig. 3BGo), but nuclear translocation of c-Jun was not observed until 6 hrs after the addition of LPS (Fig. 3EGo). However, co-culture of LPS-stimulated cells with VIP 10–8 M inhibited nuclear translocation of both NF{kappa}B (Fig. 3CGo) and c-Jun (Fig. 3FGo).



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  		Figure 3. Subcellular location of transcription factors (NF{kappa}B or c-Jun) in THP1 monocytes. Cells were analyzed after incubation in medium alone (A,D), following treatment with 100 ng/mL Pg W50 LPS (B,E), and with 100 ng/mL Pg LPS with VIP (10–8 M).(C,F) Fluorescently labeled antibodies were used to detect NF{kappa}B (green fluorescence) and c-Jun (red fluorescence), and sections were analyzed by confocal laser scanning microscopy. Nuclei were counter-stained with DAPI (blue fluorescence). Each image was taken between 6 and 8 µm through the cells, so that the nuclei could be clearly determined. Scale bar in bottom left corner = 30 µm. Each result was replicated on at least 6 separate occasions.

 
Pg LPS Does Not Affect CD14 Expression in THP1 Monocytes
Our results showed that culture of THP1 cells with 100 ng/mL P. gingivalis LPS (Fig. 4CGo) or co-culture of cells with LPS and VIP (Fig. 4DGo) did not affect cell surface CD14 expression, and that CD14 expression as a result of both these treatments was comparable with that measured on the surfaces of unstimulated cells (Fig. 4BGo).



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  		Figure 4. CD14 expression on THP-1 monocytes following exposure to LPS. (A) Isotype control (IgG2a. PE). (B) Unstimulated THP1 cells (negative control). (C) THP1 cells stimulated with Pg LPS (100 ng/mL) for 6 hrs. (D) THP1 cells stimulated with LPS and VIP (10–8 M). CD14 expression was determined by flow cytometry. The upper-right-quadrant highly granular cells express CD14, and the upper-left-quadrant low-granular cells express CD14. The figures in the dot-blots represent the proportion of the total cell number in each of these upper quadrants. This experiment is representative of similar results obtained on at least 8 separate occasions.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We showed, for the first time, that inflammatory responses produced by human monocytic THP1 cells in response to Pg LPS are ameliorated by VIP. This was observed by VIP-induced inhibition of TNF-{alpha} production and could not be accounted for by differential rates of cell death. TNF-{alpha} is a particularly relevant cytokine to study in the context of periodontal disease, since it is produced by human monocytes stimulated with Pg LPS (Lindemann et al., 1988; McFarlane et al., 1990), it has been isolated from the GCF of patients with clinical disease (Rossomando et al., 1990; Graves and Cochran, 2003), and it causes alveolar bone resorption (Graves and Cochran, 2003). Our results showed that THP1 monocytes are highly sensitive to Pg LPS, since LPS at concentrations as low as 1 ng/mL induced significant production of TNF-{alpha}.

Transfection of human macrophages with plasmids carrying dominant-negative NF{kappa}B or c-Jun inhibits LPS-induced TNF-{alpha} production, thus highlighting the importance of both transcription factors in TNF-{alpha} responses (Liu et al., 2000). We showed that nuclear translocation of NF{kappa}B and c-Jun was induced by Pg LPS within 90 min and 6 hrs, respectively, and that this was inhibited when THP1 monocytes were co-cultured with LPS and VIP. This suggests that the inhibition of TNF-{alpha} by VIP could be due to inhibition of NF{kappa}B and c-Jun translocation. We also showed that VIP had a prolonged inhibitory effect (at least 6 hrs) on transcription factor activity. VIP changes the biochemical nature of Activator Protein-1 (AP-1), such that c-Jun/c-Fos heterodimers are replaced by Jun B/c-Fos heterodimers, causing decreased binding to the TNF-{alpha} promoter, while VIP inhibits nuclear translocation of NF{kappa}B by increasing I{kappa}B stability (Delgado and Ganea, 2000). VIP also inhibits IL-8 production by E. coli LPS-stimulated THP1 cells (Delgado and Ganea, 2003), which was one of the few studies, to date, to investigate the effect of VIP on human monocytes. Our results are in accordance with these studies, but we additionally showed temporal separation of nuclear translocation of c-Jun and NF{kappa}B proteins following stimulation of THP1 cells by Pg LPS. This effect also occurs in murine macrophages stimulated with Salmonella typhimurium LPS (unpublished observations).

Previous studies have suggested that CD14 is shed from the surfaces of macrophages exposed to Pg outer membrane vesicles containing bacterial proteases (Duncan et al., 2004), thus suggesting that CD14 shedding may be a mechanism used by Pg to prevent immune detection. However, patients with periodontal disease showed increased CD14 expression on peripheral blood monocytes (Nagasawa et al., 2004), indicating that CD14 is an important receptor in the in vivo engagement of LPS from oral pathogens. VIP-induced CD14 shedding on the surfaces of murine macrophages has also been reported (Delgado et al., 1999a). We showed that CD14 levels on THP1 cells were not altered by culture of cells with Pg LPS (100 ng/mL), nor was CD14 expression decreased by co-culture of cells with LPS and VIP, and thus the initial inhibitory action of VIP was not at the point of LPS/CD14 engagement. The reason why our results differed from some of these previous observations may relate to species differences, or to the fact that these previous authors measured CD14 expression 1 hr after exposure to LPS (Delgado et al., 1999a). We are currently investigating the effect of VIP on other receptors associated with Pg LPS responses, e.g., Toll-like receptors 2 and 4.

Our results led us to hypothesize that VIP isolated in GCF from inflamed periodontal pockets (Linden et al., 2002) may be produced to dampen LPS-induced inflammation, and, as such, may represent a novel immunoregulatory circuit relevant to periodontal pathogenesis. Furthermore, the pro-inflammatory response is a rational target for periodontal treatment (Paquette and Williams, 2000), and, therefore, our results highlight the potential of VIP as an immunomodulator which may have therapeutic benefit in periodontal disease.


   ACKNOWLEDGMENTS
 
The authors thank Dr. Trevor Booth, University of Newcastle upon Tyne, for his expert assistance with confocal microscopy. This study was supported by a UK Department of Health Clinician Scientist Award, awarded to PMP (grant number DHCS/03/G121/46).

Received May 13, 2005; Last revision July 15, 2005; Accepted July 19, 2005


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 DISCUSSION
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