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The Journal of Immunology, 2003, 171: 3913-3917.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Cyclooxygenase-2 Activation Suppresses Th1 Polarization in Response to Helicobacter pylori 1

Frank Meyer2,*, Kalathur S. Ramanujam*, Alain P. Gobert*,{ddagger}, Stephen P. James*,{ddagger} and Keith T. Wilson3,*,{dagger},{ddagger}

* Division of Gastroenterology, Department of Medicine, and {dagger} Greenebaum Cancer Center, University of Maryland School of Medicine, and {ddagger} Veterans Affairs Maryland Health Care System, Baltimore, MD 21201


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Helicobacter pylori infection causes a Th1-driven mucosal immune response. Cyclooxygenase (COX)-2 is up-regulated in lamina propria mononuclear cells in H. pylori gastritis. Because COX-2 can modulate Th1/Th2 balance, we determined whether H. pylori activates COX-2 in human PBMCs, and the effect on cytokine and proliferative responses. There was significant up-regulation of COX-2 mRNA and PGE2 release in response to H. pylori preparations. Addition of COX-2 inhibitors or an anti-PGE2 Ab resulted in a marked increase in H. pylori-stimulated IL-12 and IFN-{gamma} production, and a decrease in IL-10 levels. Addition of PGE2 or cAMP, the second messenger activated by PGE2, had the opposite effect. Similarly, stimulated cell proliferation was increased by COX-2 inhibitors or anti-PGE2 Ab, and was decreased by PGE2. Our findings indicate that COX-2 has an immunosuppressive role in H. pylori gastritis, which may protect the mucosa from severe injury, but may also contribute to the persistence of the infection.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Helicobacter pylori is a Gram-negative, microaerophilic bacterium, which selectively colonizes the mammalian stomach, and causes gastritis, peptic ulcers, and gastric cancer. The human host mounts a vigorous innate and adaptive immune response, yet this results only in lifelong gastritis without eradication of the organism. H. pylori has evolved several strategies to enhance its own survival in the face of this immune response. For example, we have reported that while the host produces NO derived from inducible NO synthase in response to soluble products of H. pylori (1, 2), an arginase enzyme expressed by the bacterium competitively inhibits host NO production and prevents NO-mediated killing (3). In addition, H. pylori induces macrophage apoptosis via activation of polyamine synthesis (4), and T cell apoptosis mediated by Fas (5), both of which are likely to also diminish the effectiveness of the immune response.

There is consistent evidence that the H. pylori-induced immune response is skewed toward a Th1 phenotype indicated by a predominance of IFN-{gamma} (6, 7, 8). This polarization has been suggested to contribute to the persistence of inflammation and to the inhibition of a possibly beneficial Th2 response. However, data has now emerged from mouse model studies using cytokine-deficient mice (9) and adoptive transfer of selected splenocytes into SCID mice (10) that an inadequate Th1 response may actually contribute to the pathogenesis of the infection. Although not studied with H. pylori infection, lymphocyte immune responses have been reported to be down-regulated by PGE2, with inhibition of both T cell proliferation and production of the Th1 cytokines IL-2 and IFN-{gamma} (11) and stimulation of Th2 cytokine production (12). This effect has been attributed to elevation of the intracellular second messenger cAMP (13).

We and others have demonstrated that the inducible form of cyclooxygenase, (COX) 4-2, is up-regulated in human H. pylori gastritis tissues and localizes to lamina propria mononuclear cells (14, 15). Increased levels of PGE2 have also been demonstrated in the infected gastric mucosa (16). Accordingly, the aim of this study was to determine whether COX-2 activation is involved in H. pylori pathogenesis via inhibition of the Th1-predominant response to the infection. Although often considered a noninvasive pathogen, H. pylori itself and CagA have both been shown to invade gastric epithelial cells (17), and H. pylori proteins, including urease, have been demonstrated in the lamina propria of infected patients (18). Therefore, we used H. pylori preparations added to human PBMCs, and found that COX-2 mRNA expression and PGE2 production were induced in these cells. Inhibition of COX-2 or neutralization of PGE2 potentiated a Th1 cytokine response and lymphocyte proliferation and reduced Th2 response, while addition of exogenous PGE2 or cAMP had the opposite effect. We suggest that induction of COX-2 may be a host defense strategy that limits mucosal inflammation, but ultimately contributes to bacterial persistence and the risk for complications from longstanding infection.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents

All the reagents for cell culture and RNA analysis were obtained from Life Technologies (Gaithersburg, MD). Recombinant H. pylori urease was obtained and used as described (2, 19). Monoclonal anti-PGE2 Ab 2B5 and MOPC21 isotype-matched (IgG) control Ab were provided by S. J. Mnich and J. P. Portanova (G. D. Searle, St. Louis, MO); 1.5 µg/ml 2B5 effectively neutralizes 1 ng/ml PGE2 (20). The COX-2 inhibitors, NS-398 and 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU), were obtained from Cayman Chemical (Ann Arbor, MI) and C. C. Chan (Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada), respectively. The cAMP analogues, dibutyryl-cAMP and 8-bromo-cAMP, were obtained from Sigma-Aldrich (St. Louis, MO) and Calbiochem-Novabiochem (La Jolla, CA), respectively. PGE2 was purchased from Sigma-Aldrich.

Cells and culture conditions

PBMCs were isolated from venous blood obtained from H. pylori-negative donors using density gradient centrifugation with Histopaque-1077 (Sigma-Aldrich) and cultured in complete RPMI 1640 medium as described (19). Cells were plated at 2 x 106 cells/ml. For the RNA experiments, six-well plates were used (2 ml/well); for all other studies, round-bottom 96-well plates (200 µl/well) were used. Cultures were maintained in a humidified atmosphere (37°C) enriched with CO2 (5%) in the presence or absence of various H. pylori preparations.

Bacteria

H. pylori strain UMAB 41 (cytotoxin-associated gene (cag)A-positive) was used and grown on Brucella agar plates containing 10% sheep blood under microaerobic conditions as described (1, 19). For experiments, H. pylori was harvested into sterile PBS and concentration was determined by OD (1, 19). Lysates were prepared with a French pressure cell (1). Intact bacteria, French press lysates (FP), and recombinant urease were used at a protein concentration of 50 µg/ml, equal to 2.28 x 108 bacteria/ml (1), because this concentration of bacterial preparations elicits a maximal cytokine response in PBMCs (19).

mRNA analysis

PBMCs were cocultured with H. pylori preparations and after incubations, cells were washed twice with PBS, and total RNA was isolated using TRIzol reagent. Reverse transcription, PCR cycle conditions, primer sequences, and digital capture of gels were as described (21).

Cytokine and PGE2 assays

Culture supernatants were immediately analyzed in triplicate for cytokine concentrations using commercially available ELISA Kits (Quantikine; R&D Systems, Minneapolis, MN) for IL-10, IL-12p40, and IFN-{gamma} (19). PGE2 was measured by enzyme immunoassay (Cayman Chemical).

Proliferation studies

Tritium incorporation was used as an estimate for cell growth and DNA synthesis as described (19). After 24 h of cell culture, 1 µCi [methyl-3H]thymidine (Amersham, Arlington Heights, IL) was added to triplicate PBMC cultures for 12 h. Incorporated radioactivity was measured in cpm by liquid scintillation counting.

Statistics

Results are expressed as mean ± SEM. For comparisons between multiple groups, the Student Newman-Keuls test was used, and for single comparisons between two groups, the Student t test was used as appropriate.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
H. pylori preparations induce COX-2 expression and activity in PBMCs

To determine whether H. pylori could up-regulate COX-2 in human mononuclear cells in vitro, we exposed freshly isolated ex vivo human PBMCs to different bacterial preparations. As shown in Fig. 1A, intact H. pylori bacteria, lysates, or recombinant urease each markedly increased COX-2 mRNA expression from undetectable basal levels. PGE2 levels were measured in response to these preparations as an indicator of COX-2 activity (Fig. 1B), with significant, 25- to 90-fold, increases detected. These increases were completely abolished by the COX-2 inhibitors NS-398 or DFU. Data with H. pylori lysate are shown; similar inhibition of PGE2 release with COX-2 inhibitors was observed with stimulation by intact H. pylori or recombinant urease.



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  		FIGURE 1. Effect of H. pylori preparations on COX-2 mRNA expression and PGE2 release in human PBMCs. Cells were cocultured with intact H. pylori (HP), FP, or recombinant urease, all at 50 µg/ml. A, RT-PCR was performed for COX-2 mRNA levels after a 6-h incubation. B, PGE2 levels were measured in culture supernatants after 24 h incubation; n = 6 separate experiments, each performed in duplicate. **, p < 0.01 vs unstimulated control; §§, p < 0.01 vs FP alone. NS-398 and DFU were used at 1 and 10 µM, respectively.

 
PGE2 inhibits IL-12 and IFN-{gamma} production and increases IL-10 response to H. pylori

Because we found that H. pylori induced PGE2 release, we sought to directly assess the effect of PGE2 on H. pylori-stimulated cells. As shown in Fig. 2A, addition of exogenous PGE2 resulted in a concentration-dependent inhibition of IL-12 and IFN-{gamma} production, by 57–92% and 68–97%, respectively, and an up-regulation of IL-10 production, by 170–360% of control values.



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  		FIGURE 2. Effect of exogenous PGE2 and cAMP on H. pylori-stimulated IL-12, IFN-{gamma}, and IL-10 response in human PBMCs. A, PGE2 was added at the concentrations shown at the time of coculture of H. pylori intact bacteria (HP) or FP; n = 3, in duplicate. *, p < 0.05; **, p < 0.01 vs no PGE2 added for HP; #, p < 0.05; ##, p < 0.01 vs no PGE2 for FP. B, Dibutyryl-cAMP was added at 0.1 mM at the start of coculture; n = 3, in duplicate. **, p < 0.01; ***, p < 0.001 vs no cAMP analog.

 
cAMP reproduces the PGE2 effect

Because PGE2 is known to activate the intracellular second messenger cAMP, we also determined whether addition of cAMP analogues could reproduce the effect of PGE2 (Fig. 2B). Dibutyryl-cAMP significantly inhibited the H. pylori-stimulated IL-12 and IFN-{gamma} production and simultaneously increased IL-10 levels, in the same pattern as observed with addition of PGE2. Similar results occurred with another cAMP analog, 8-bromo-cAMP (data not shown).

COX-2 expression and PGE2 production down-regulate Th1 and enhance Th2 response to H. pylori

Because we found that H. pylori induced COX-2, we sought to determine whether the functional activity of COX-2 resulted in modulation of the Th1-driven immune response to H. pylori. Inhibition of COX-2 with NS-398 resulted in a significant further increase in both IL-12 and IFN-{gamma} levels above that due to stimulation with H. pylori alone (Fig. 3, top and middle panels), indicative of a potentiation of the Th1-like response. This occurred in a similar fashion with all three preparations of H. pylori. Similar results were observed with COX-2 inhibition by DFU (data not shown). Additionally, neutralizing Ab to PGE2, the main COX-2 product in mononuclear cells, effectively increased the IL-12 and IFN-{gamma} production as well (Fig. 3). Importantly, both NS-398 and anti-PGE2 Ab decreased the IL-10 response to the three H. pylori preparations (Fig. 3, bottom panel). Taken together, these data suggest that COX-2 activity, and generation of PGE2, specifically, normally act to limit Th1 response and enhance Th2 response.



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  		FIGURE 3. Inhibition of COX-2 activity or neutralization of endogenous PGE2 exacerbates Th1 polarization in response to H. pylori. Intact HP, FP lysates, and recombinant urease were each used to stimulate PBMCs for 24 h in the absence and presence of the 1 µM COX-2 inhibitor NS-398, 135 µg/ml anti-PGE2 Ab 2B5, or 135 µg/ml control IgG Ab MOPC21. Cytokine data are shown as the percentage of the stimulated control (H. pylori preparations alone) to allow for variation in baseline and stimulated cytokine production between experiments using the different inhibitors; n = 3, in duplicate. *, p < 0.05; **, p < 0.01 vs stimulated control (no inhibitor); §, p < 0.05; §§, p < 0.01 vs control Ab.

 
COX-2 inhibits lymphocyte proliferation in response to H. pylori products via PGE2 synthesis

Because lymphocyte proliferation is an important part of the amplification of the mucosal immune response, we determined whether COX-2 activity could also regulate this process. We studied modulation of proliferation induced by recombinant urease at 50 µg/ml, because we previously reported that urease was a more potent inducer of proliferation than intact or lysed H. pylori and that this was the concentration at which peak stimulation occurred (19). Addition of PGE2 caused a concentration-dependent 44–82% inhibition of proliferation (Fig. 4A). Consistent with this, addition of NS-398 or neutralization of PGE2 resulted in a significant 3- to 4-fold increase in cell proliferation (Fig. 4B). Similar results occurred with COX-2 inhibition by DFU (data not shown).



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  		FIGURE 4. COX-2 activity regulates H. pylori urease-stimulated cell proliferation in PBMCs, as determined by uptake of [3H]thymidine. A, Addition of PGE2 inhibits proliferation. B, Neutralization of endogenous PGE2 or inhibition of COX-2 increases proliferation; anti-PGE2 Ab 2B5, control Ab MOPC21, and NS-398 were added as in Fig. 2. A, Values are mean cpm ± SEM; B, data are standardized to the cpm attributable to urease stimulation, to allow for variation in baseline and stimulated proliferation between experiments using the different inhibitors. For A and B, n = 3, in triplicate. A, **, p < 0.01 vs control without urease; §§, p < 0.01 vs urease alone. B, **, p < 0.01 vs urease alone.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
COX-2 has gained extensive notoriety as a proneoplastic factor, which has been attributed to factors such as inhibition of epithelial apoptosis (22), stimulation of proliferation (23), and angiogenesis (24). We and others have shown that H. pylori increases COX-2 expression in human gastric mucosa (14, 15) and in gastric epithelial cell lines (21, 25). H. pylori is strongly linked to gastric cancer (26), and the chronic inflammation associated with the longstanding infection is presumed to be the main cause. It has been suggested that chronic overexpression of COX-2 may be a contributing factor in this process via effects on epithelial cells (21, 25). We now present new evidence that an important role of COX-2 in H. pylori pathogenesis is also dysregulation of the immune response. Using human PBMCs exposed to various H. pylori preparations, we show that COX-2 is potently induced in these cells and the resulting PGE2 production causes attenuation of IL-12 and IFN-{gamma} production and lymphocyte proliferation, and enhancement of IL-10 response.

It is expected that the primary source of COX-2 and PGE2 production in the PBMCs is monocytes; consistent with this, we have observed significant COX-2 expression and activity in mouse macrophage cell lines, peritoneal macrophages, and splenocytes (27). However, inducible PGE2 production by lymphocytes has also been reported (28). Our data indicate that urease is a potent inducer of COX-2 expression; consistent with this we have found that concentrated supernatants of ureA-deficient isogenic mutant strains have decreased COX-2 inducing activity in mouse macrophages (27) and we have reported that urease is a major inducer of iNOS expression in macrophages (2). Additionally, our data are expected to have direct relevance to the events in the gastric mucosa, because we have observed that COX-2-/- mice infected with H. pylori have both increased gastritis and up-regulated IFN-{gamma} and IL-12 expression compared with wild-type mice (29). It is also likely that the presence of both monocytes and lymphocytes in the PBMCs provides a synergistic effect in the H. pylori response. For example, IL-12 is primarily derived from monocytes and acts to induce IFN-{gamma} synthesis by lymphocytes, as evidenced by our previous report that neutralization of IL-12 can inhibit H. pylori-stimulated IFN-{gamma} production (19). Although the mucosal response to H. pylori is Th1-predominant, Th2 cytokine generation by T cell clones derived from H. pylori-infected hosts has been demonstrated in a substantial number of cases (7, 30), consistent with our findings of H. pylori induced IL-10 response in this study and in our prior report (19). Therefore, the ability of COX-2 to modulate both the Th1 and Th2 cytokine response, as we have shown in this report, is likely to be significant.

It is probable that H. pylori may often behave as a commensal organism that more frequently exerts a pathological role in the case of strains possessing the cag pathogenicity island or in unusually susceptible hosts (31, 32). A common feature of the infection is chronic persistent gastritis, and inability of the host to eradicate the organism despite the mucosal immune response (31, 32). We suggest that our data may explain, at least in part, the persistence of the bacterium. Mouse studies have directly shown that Th1 responses are associated with increased gastritis, because IFN-{gamma}-/- mice had decreased gastritis (9) and SCID mice infected with H. pylori required reconstitution with CD4+ T cells for gastritis, with inflammation most severe in mice receiving splenocytes from IL-10-/- mice and least severe with cells received from IFN-{gamma}-/- mice (10). However, these studies have also elucidated the critical point that a decreased Th1 response is associated with increased bacterial colonization. IFN-{gamma}-/- and IL-12-/- mice could not be immunized against H. pylori infection, in contrast to wild-type or Th2-deficient IL-4-/- mice (9). Additionally, SCID mice adoptively transferred with varying splenocyte preparations exhibited an inverse correlation between severity of gastritis associated with Th1 response and bacterial colonization (10). We conclude that the chronic expression of COX-2 and production of PGE2 in mononuclear and other cells of the gastric mucosa results in inhibition of the effectiveness of the mucosal immune response by enhancing a state of tolerance (33) that may prevent eradication of the organism and contribute to the risk for complications from H. pylori infection, including gastric cancer.


   Footnotes
 
1 This work was supported by National Institutes of Health Grants DK53620 (to K.T.W. and S.P.J.), DK 02469 (to K.T.W.), and DK56938 (to K.T.W.), Deutsche Forschungsgemeinschaft Grant Me 1400/1-1 (to F.M.), and the Office of Medical Research, Department of Veterans Affairs (to K.T.W.). Back

2 Current address: Department of Surgery, University Hospital, Otto von Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany. Back

3 Address correspondence and reprint requests to Dr. Keith T. Wilson, Division of Gastroenterology, Department of Medicine, University of Maryland School of Medicine, 22 South Greene Street, Room N3W62, Baltimore, MD 21201. E-mail address: kwilson@umaryland.edu Back

4 Abbreviations used in this paper: COX, cyclooxygenase; cag, cytotoxin-associated gene; FP, French press lysate. Back

Received for publication May 30, 2003. Accepted for publication August 13, 2003.


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 Introduction
 Materials and Methods
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