SEARCH

SEARCH BY CITATION

Keywords:

  • Helicobacter pylori;
  • Cytokine;
  • Cell marker;
  • Chronic inflammation;
  • Activity;
  • Helicobacter pylori density

Abstract

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Materials and methods
  5. 3Results
  6. 4Discussion
  7. Acknowledgements
  8. References

Helicobacter pylori is an important pathogen in gastroduodenal inflammation and ulceration. Several mechanisms have been proposed to explain its role. We studied the cytokine production patterns in situ in gastric mucosal biopsies from H. pylori-positive and H. pylori-negative patients with dyspepsia. Immunohistochemistry with monoclonal antibodies was used. The study showed enhanced expression of interleukin (IL) -8, IL-10 and interferon-γ (IFN-γ) in H. pylori infection and a significant association was found between these cytokines and the following parameters: bacteria load, chronic inflammation and activity. These parameters were significantly correlated with the cell markers CD19 and CD56. The study indicates a dual effect of H. pylori on the Th1 response, i.e. a stimulation of the response verified by increased IFN-γ and a feed-back verified by an increase of the counterinflammatory IL-10, which may dampen the inflammatory and cytotoxic effect of the Th1 response. Furthermore, the study confirms the connection between increase of IL-8 and inflammatory activity in gastric mucosa in H. pylori infection.


1Introduction

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Materials and methods
  5. 3Results
  6. 4Discussion
  7. Acknowledgements
  8. References

Helicobacter pylori is an important pathogenic factor in chronic active gastritis, duodenal and gastric ulcers [1–3], and invasion of H. pylori is supported by the presence of the organism in epithelial cells and lamina propria [4,5]. Infection with this organism induces infiltration of polymorphonuclear (PMN) and mononuclear leukocytes and enhances the production of various proinflammatory cytokines in gastric mucosa [6–9]. Among these cytokines, enhanced mRNA expression and protein secretion for interleukin (IL) -8, a neutrophil chemotactic factor, were observed in H. pylori-positive gastritis compared with H. pylori-negative controls [10,11]. A prominent finding in H. pylori infection is the enhancement of interferon-γ (IFN-γ) production in cell cultures stimulated with H. pylori products [12–14]. Additionally, an increased number of gastric T cells expressing INF-γ was observed [13,15]. These in vitro studies suggest a predominance of Th1 response in H. pylori infection, which may be involved in the pathogenesis of gastritis and ulcer in H. pylori-positive patients.

Recently, some investigators have focused on the antiinflammatory cytokine IL-10, which is known to inhibit the synthesis of proinflammatory cytokines [16–18]. In organ cultures enhanced secretion of IL-10 was found in H. pylori-infected individuals compared to non-infected subjects [19,20]. Furthermore, IL-10 mRNA was detected in biopsy specimens from H. pylori-positive gastritis with severe infiltration of PMN [11]. In vitro stimulation with H. pylori also enhanced the IL-10 secretion by peripheral blood mononuclear cells (PBMC) from H. pylori-infected patients [21].

In all these experiments, except for mRNA expression, the cytokine pattern was studied in vitro and during various conditions, including the addition of H. pylori products, and a possible association with bacteria load and gastric inflammation was not examined. Therefore, the aim of this study was to examine the gastric mucosal cytokine activity in situ at the tissue level in relation to the H. pylori status and the parameters mentioned.

2Materials and methods

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Materials and methods
  5. 3Results
  6. 4Discussion
  7. Acknowledgements
  8. References

2.1Subjects

Fifty-five dyspeptic patients (31 males and 24 females, mean age 51 years, range 19–84 years) attending for diagnostic endoscopy were studied. All patients gave informed consent and the study was in accordance with the second Helsinki declaration and was approved by the local ethics committee.

None of the patients had received antibiotics, bismuth compounds, H2 antagonists and proton pump inhibitors at least for 1 or 2 weeks before the endoscopy. Patients who had received corticosteroids or immunosuppressive drugs or who showed a history of malignancy or immunosuppression were excluded.

2.2Biopsy samples, histology and H. pylori status

Three gastric (antral) biopsies were obtained during each gastroscopy: one for culture, one was frozen for immunohistochemistry, and one was formalin-fixed, paraffin-embedded for routine histology. The number of biopsies seems to be sufficient since antral gastritis is a diffuse lesion. Culture was performed to verify the presence or absence of H. pylori in gastric mucosa. Therefore, biopsies were cultured on 7% lysed horse blood agar plates by incubation at 37°C under microaerobic conditions for <7 days. H. pylori was identified as oxidase-, catalase- and urease-positive, Gram-negative curved rods.

For immunohistochemistry snap-frozen biopsies were cut with a cryostat in 7-μm sections and air-dried overnight at room temperature before immunostaining. Monoclonal antibodies recognising the cytokines (R&D Systems) and cell markers (Dako, Denmark) were used as primary antibodies and immunostaining was performed using a sensitive biotin–avidin immunoperoxidase method (ABComplex/HRP staining procedure, Dako, Denmark). The sections were counterstained with haematoxylin–eosin to identify the cell types.

The immunoreaction was graded semiquantitatively. For IL-8-stained sections (Fig. 1A) a score was assigned to the foveolar/surface epithelium: 0 (absent) to 3 (severe). For IL-10 (Fig. 1B) and INF-γ, scores were assigned to the mononuclear cells (MNC) in the lamina propria: 0 (absent), 1 (few, roughly <10% MNC), 2 (moderate, ∼10–50% MNC) and 3 (numerous, i.e. >50%).

image

Figure 1. Immunohistochemistry with monoclonal antibodies to detect cytokines. Immunoreaction for IL-8 is located to the foveolar epithelium (arrows) (A) and scattered inflammatory cells (arrows) in the lamina propria are immunopositive for IL-10 (B).

Download figure to PowerPoint

For routine histology, haematoxylin–eosin-stained paraffin-embedded sections were scored semiquantitatively on a visual analogue scale [7] for inflammatory activity (PMN), chronic inflammation (lymphocytes, plasma cells) and H. pylori density, graded from 0 (absent) to 3 (extensive). All histology was performed by S.H. and blinded to the clinical/endoscopic findings.

2.3Statistical analysis

Fisher's exact test was used to verify a significant association between cytokines or cell markers and inflammatory activity, chronic inflammation or H. pylori density. P<0.05 was regarded as significant. Mean and error bars: 95% confidence interval are given.

3Results

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Materials and methods
  5. 3Results
  6. 4Discussion
  7. Acknowledgements
  8. References

3.1H. pylori status, gastroscopy and histology

The patient characteristics are given in Table 1. H. pylori status obtained from cultured biopsies showed that 37 patients were H. pylori-positive and 18 H. pylori-negative. The H. pylori status was in agreement with the scores of H. pylori density, except for two patients. Thus, H. pylori-negative patients showed a H. pylori density score of 0, whereas H. pylori-positive patients showed scores from 1 to 3. Gastroscopy showed normal mucosa in 26 patients, gastritis or oesophagitis in 13 patients and 16 patients had ulcer. Histologic examination showed that 16 patients had chronic inactive gastritis (inflammatory activity: score 0), 23 showed chronic active gastritis (inflammatory activity: scores 1–3) and 16 showed normal mucosa (chronic inflammation: scores 0 or 1, inflammatory activity: score 0).

Table 1.  Patient characteristics (n=55)
Profilen
Sex (males/females)31/24
H. pylori status (culture) positive/negative37/18
Gastroscopy 
Normal mucosa26
Gastritis/oesophagitis10/3
Ulcer (duodenal/prepyloric/gastric)8/5/3
Histology 
Normal mucosa16
Gastritis (inactive/active)16/23

3.2H. pylori load and degree of inflammatory reaction

A significant association was found between H. pylori density and the inflammatory activity in the gastritis group (active and inactive) as well as in the total population of patients (P<0.01) (Fig. 2). In both groups of patients a significant correlation was also obtained between the bacteria load and chronic inflammation and furthermore between chronic inflammation and activity (P<0.01).

image

Figure 2. H. pylori density as a function of inflammatory activity. A statistically significant positive correlation between the scores is seen: correlation coefficient 0.848, P<0.01 (Fisher's exact test). Error bars: 95% confidence interval. Note that score 0 on the x- and y-axes was obtained by the H. pylori-negative individuals whereas all the H. pylori-positive patients, except for two patients, showed higher scores indicated in the columns.

Download figure to PowerPoint

3.3Cytokine activity and the degree of inflammation and bacteria load

The gastric mucosal cytokine response and gastric inflammation was examined in the entire study group as well as in the gastritis patients. The in situ expression of cytokine graded from 0 to 3 was compared with the scores of inflammatory activity. A significant association between IL-8 and inflammatory activity was obtained in both groups of patients (P<0.01). Fig. 3 shows the results from the total population of patients. A significant association was also obtained with chronic inflammation in gastritis patients (P<0.05), but not in the entire study group. IFN-γ and IL-10 showed a similar correlation with activity as well as with chronic inflammation in both groups of patients (P<0.01). The association with activity in the entire group of patients is given in Figs. 4 and 5. In both groups, IL-8, IL-10 and IFN-γ were significantly correlated with the H. pylori density (P<0.01).

image

Figure 3. IL-8 expression as a function of inflammatory activity. A statistically significant positive correlation between the scores is seen: correlation coefficient 0.385, P<0.01 (Fisher's exact test). Error bars: 95% confidence interval. Note that score 0 in inflammatory activity was obtained by H. pylori-negative individuals except for two patients.

Download figure to PowerPoint

image

Figure 4. IFN-γ expression as a function of inflammatory activity. A statistically significant positive correlation between the scores is seen: correlation coefficient 0.447, P<0.01 (Fisher's exact test). Error bars: 95% confidence interval. Note that score 0 in inflammatory activity was obtained by H. pylori-negative individuals except for two patients.

Download figure to PowerPoint

image

Figure 5. IL-10 expression as a function of inflammatory activity. A statistically significant positive correlation between the scores is seen: correlation coefficient 0.406, P<0.01 (Fisher's exact test). Error bars: 95% confidence interval. Note that score 0 in inflammatory activity was obtained by H. pylori-negative individuals except for two patients.

Download figure to PowerPoint

3.4Cell markers and degree of inflammation and bacteria load

The composition of the cellular infiltrate in gastric mucosa was studied using the following cell markers: CD4 (Th), CD8 (Tc), CD14 (monocytes), CD19 (B cells) and CD56 (K/NK). The in situ activity of the markers scored from 0 to 3 was compared to inflammatory activity, chronic inflammation and H. pylori density. In the total population of patients all cell markers, except for CD8, were significantly correlated with activity, chronic inflammation and bacteria load (P<0.05). CD8 was associated only with chronic inflammation. In gastritis patients, a significant correlation with activity, chronic inflammation and H. pylori density was found for CD19 and CD56, and CD14 was associated with chronic inflammation (P<0.05).

3.5Prevalence of cytokine response in H. pylori-positive and -negative patients

The cytokine activity for IL-8, IFN-γ and IL-10 was enhanced in H. pylori-infected patients. Thus, higher cytokine scores (2–3) were found in half of the H. pylori-positive patients, whereas these scores were obtained in only up to 25% of the H. pylori-negative subjects (data not shown).

4Discussion

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Materials and methods
  5. 3Results
  6. 4Discussion
  7. Acknowledgements
  8. References

The association between inflammatory activity and chronic inflammation as well as the positive correlation between inflammation (active and chronic) and bacteria load were expected and in accordance with earlier studies of gastric dyspepsia in H. pylori-infected patients [22], indicating a role of the organism for gastric inflammation. Additional support for this view was the finding of a significant correlation between bacteria load and markers of inflammatory cells.

Our in situ study showed enhanced IFN-γ expression in gastric mucosa in H. pylori-infected patients, confirming the results of Lindholm et al. [23], and studies of biopsy cultures [12–14]. This IFN-γ activity was associated with the H. pylori density and correlated significantly with inflammation (active and chronic). These results and the prominence of inflammatory cells in gastric mucosa in H. pylori-infected patients point to a possible predominance of the Th1 response in H. pylori infection, as suggested by studies of frequency and phenotype of IFN-γ- and IL-4-producing T cells [13] and by the increase in IFN-γ-secreting cells in gastritis compared to patients with no gastritis [24]. Furthermore, the hypothesis has been supported by experiments on mice [25–28].

The pathogenic mechanisms causing inflammation and epithelial destruction may therefore include a Th1 response. However, non-immunological mechanisms should also be considered since PBMC and whole-blood cultures from H. pylori-negative individuals caused increased IFN-γ secretion by in vitro stimulation with H. pylori or its products [14,29]. Experiments on gastric epithelial cell lines indicate that IFN-γ production could increase class II MHC expression on the epithelium leading to increased H. pylori attachment and possible induction of epithelial cell apoptosis [31], but other apoptotic pathways should also be taken into account [32–34].

IL-8, belonging to the CXC family of chemokines, has chemotactic and activating properties for neutrophils and may therefore influence development of gastric disease. Our in situ study shows a higher prevalence of IL-8 activity in H. pylori-positive patients than in H. pylori-negative individuals, a finding in accordance with organ cultures [10,30] and expression of IL-8 mRNA [11]. The correlation between IL-8 expression and the scores of inflammatory activity and bacteria load also supports the results from organ cultures [10].

H. pylori-positive individuals showed a higher prevalence of high IL-10 activity than uninfected individuals in accordance with data from organ cultures [19,20]. Furthermore, an association was found between the IL-10 activity and the scores of inflammatory activity, chronic inflammation and bacteria load. Since IL-10 is known to inhibit the synthesis of IFN-γ[18] as well as IL-1, IL-6, IL-8 and tumour necrosis factor-α[35], IL-10 may dampen the inflammation and cytotoxic effect of these cytokines.

In conclusion, our results indicate a dual effect of H. pylori on the Th1 response, i.e. a stimulation of the response verified by increased IFN-γ and a feed-back (possible downregulation of IFN-γ) verified by an increase of the counterinflammatory IL-10, which may dampen the inflammatory and cytotoxic effect of the Th1 response. Furthermore, the study confirms the connection between increase of IL-8 and PMN infiltration in gastric mucosa in H. pylori infection.

Acknowledgements

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Materials and methods
  5. 3Results
  6. 4Discussion
  7. Acknowledgements
  8. References

This study was supported by the foundations Direktør E. Danielsen og Hustrus Fond, Ludvig og Fransiska Andersens Legat and Den lægevidenskabelige forskningsfond for Storkøbenhavn, Færøerne og Grønland. The technical assistance of Lis Christiansen is gratefully acknowledged.

References

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Materials and methods
  5. 3Results
  6. 4Discussion
  7. Acknowledgements
  8. References
  • [1]
    Graham, D.Y., Malaty, H.M., Evans, D.G. D.J. Evans 3rd Klein, P.D., Adam, E. (1991) Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Effect of age, race, and socioeconomic status. Gastroenterology 100, 14951501.
  • [2]
    Korman, M.G., Marks, I.N., Hunt, R.H., Axon, A., Blaser, M.J., McCarthy, D.M., Tytgat, G.N.J. (1993) Helicobacter pylori: a workshop review. Eur. J. Gastroenterol. Hepatol. 5, 963967.
  • [3]
    Kreiss, C., Blum, A.L., Malfertheiner, P. (1995) Peptic ulcer pathogenesis. Curr. Opin. Gastroenterol. 11, 2531.
  • [4]
    Bode, G., Malfertertheiner, P., Ditschuneit, H. (1987) Invasion of Campylobacter-like organisms in the duodenal mucosa in patients with active duodenal ulcer. Klin. Wochenschr. 65, 144146.
  • [5]
    Andersen, L.P., Holck, S. (1990) Possible evidence of invasiveness of Helicobacter (Campylobacter) pylori. Eur. J. Clin. Microbiol. Infect. Dis. 9, 135138.
  • [6]
    Fan, X-G., Chua, A., Fan, X-J., Keeling, P.W.N. (1995) Increased gastric production of interleukin-8 and tumour necrosis factor in patients with Helicobacter pylori infection. J. Clin. Pathol. 48, 133136.
  • [7]
    Dixon, M.F., Genta, R.M., Yardley, J.H., Correa, P., Participants in the International Workshop on the Histopathology of Gastritis, Houston 1994 (1996) Classification, grading of gastritis. The updated Sydney System. Am. J. Surg. Pathol. 20, 1161–1181.
  • [8]
    Noach, L.A., Bosma, N.B., Jansen, J., Hoek, F.J., van Deventer, S.J., Tytgat, G.N. (1994) Mucosal tumor necrosis factor α, interleukin-1β, and interleukin-8 production in patients with Helicobacter pylori infection. Scand. J. Gastroenterol. 29, 425429.
  • [9]
    Hida, N. T. Shimoyama 3rd Neville, P., Dixon, M.F., Axon, A.T.R. T. Shimoyama 3rd Crabtree, J.E. (1999) Increased expression of IL-10 and IL-12 (p40) mRNA in Helicobacter pylori infected gastric mucosa: relation to bacterial cag status and peptic ulceration. J. Clin. Pathol. 52, 658664.
  • [10]
    Ando, T., Kusugami, K., Ohsuga, M., Shinoda, M., Sakakibara, M., Saito, H., Fukatsu, A., Ichiyma, S., Ohta, M. (1996) Interleukin-8 activity correlates with histological severity in Helicobacter pylori-associated antral gastritis. Am. J. Gastroenterol. 91, 11501156.
  • [11]
    Yamaoka, Y., Kita, M., Kodama, T., Sawai, N., Kashima, K., Imanishi, J. (1995) Expression of cytokine mRNA in gastric mucosa with Helicobacter pylori infection. Scand. J. Gastroenterol. 30, 11531159.
  • [12]
    Quiding-Järbrink, M., Lundin, B.S., Lönroth, H., Svennerholm, A.-M. (2001) CD4+ and CD8+ T cell responses in Helicobacter pylori-infected individuals. Clin. Exp. Immunol. 123, 8187.
  • [13]
    Bamford, K.B., Fan, X., Crowe, S.E., Leary, J.F., Gourley, W.K., Luthra, G.K., Brooks, E.G., Graham, D.Y., Reyes, V.E., Ernst, P.B. (1998) Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype. Gastroenterology 114, 482492.
  • [14]
    Ren, Z., Pang, G., Lee, R., Batey, R., Dunkley, M., Borody, T., Clancy, R. (2000) Circulating T-cell response to Helicobacter pylori infection in chronic gastritis. Helicobacter 5, 135141.
  • [15]
    Agnihotri, N., Bhasin, D.K., Vohra, H., Ray, P., Singh, K., Ganguly, N.K. (1998) Characterization of lymphocytic subsets and cytokine production in gastric biopsy samples from Helicobacter pylori patients. Scand. J. Gastroenterol. 33, 704709.
  • [16]
    Fiorentino, D.F., Zlotnik, A., Mosmann, T.R., Howard, M., O'Garra, A. (1991) IL-10 inhibits cytokine producyion by activated macrophages. J. Immunol. 147, 38153822.
  • [17]
    De Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C.G., De Vries, J.E. (1991) Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 12091220.
  • [18]
    Vieira, P., De Waal-Malefyt, R., Dang, M.-N., Johnson, K.E., Kastelein, R., Fiorentino, D.F., De Vries, J.E., Roncarolo, M.-G., Mosmann, T.R., Moore, K.W. (1991) Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc. Natl. Acad. Sci. USA 88, 11721176.
  • [19]
    Bauditz, J., Ortner, M., Bierbaum, M., Niedobitek, G., Lochs, H., Schreiber, S. (1999) Production of IL-12 in gastritis relates to infection with Helicobacter pylori. Clin. Exp. Immunol. 117, 316323.
  • [20]
    Bodger, K., Wyatt, J.I., Heatley, R.V. (1997) Gastric mucosal secretion of interleukin-10: relations to histopathology, Helicobacter pylori status, and tumour necrosis factor-α secretion. Gut 40, 739744.
  • [21]
    Jacob, B., Birkholz, S., Schneider, T., Duchmann, R., Zeitz, M., Stallmach, A. (2001) Immune response to autologous and heterologous Helicobacter pylori antigens in humans. Microsc. Res. Tech. 53, 419424.
  • [22]
    Stolte, M., Stadelmann, O., Bethke, B., Burkard, G. (1995) Relationships between the degree of Helicobacter pylori colonisation and the degree and activity of gastritis, surface epithelial degeneration and mucus secretion. Z. Gastroenterol. 33, 8993.
  • [23]
    Lindholm, C., Quiding-Järbrink, M., Lönroth, H., Hamlet, A., Svennerholm, A.-M. (1998) Local cytokine response in Helicobacter pylori-infected subjects. Infect. Immun. 66, 59645971.
  • [24]
    Karttunen, R., Karttunen, T., Ekre, H-P.T., MacDonald, T.T. (1995) Interferon gamma and interleukin 4 secreting cells in the gastric antrum in Helicobacter pylori positive and negative gastritis. Gut 36, 341345.
  • [25]
    Eaton, K.A., Mefford, M., Thevenot, T. (2001) The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice. J. Immunol. 166, 74567461.
  • [26]
    Sommer, F., Faller, G., Röllinghoff, M., Kirchner, T., Mak, T.W., Lohoff, M. (2001) Lack of gastritis and of an adaptive immune response in interferon regulatory factor-1 deficient mice infected with Helicobacter pylori. Eur. J. Immunol. 31, 396402.
  • [27]
    Mohammadi, M., Czinn, S., Redline, R., Nedrud, J. (1996) Helicobacter-specific cell-mediated immune responses display a predominant Th1 phenotype and promote a delayed-type hypersensitivity response in the stomachs of mice. J. Immunol. 156, 47294738.
  • [28]
    Bennedsen, M., Wang, X., Willén, R., Wadström, T., Andersen, L.P. (1999) Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol. Lett. 70, 185189.
  • [29]
    Meyer, F., Wilson, K.T., James, S.P. (2000) Modulation of innate cytokine responses by products of Helicobacter pylori. Infect. Immun. 68, 62656272.
  • [30]
    Bodker, K., Bromelow, K., Wyatt, J.I., Heatley, R.V. (2001) Interleukin 10 in Helicobacter pylori associated gastritis: immunohistochemical localisation and in vitro effects on cytokine secretion. J. Clin. Pathol. 54, 285292.
  • [31]
    Fan, X., Crowe, S.E., Behar, S., Gunasena, H., Ye, G., Haeberle, H., van Houten, N., Gourley, W.K., Ernst, P.B., Reyes, V.E. (1998) The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage. J. Exp. Med. 187, 16591669.
  • [32]
    Ishihara, S., Fukuda, R., Kawashima, K., Morijyama, N., Suetsugu, H., Ishimura, N., Kazumori, H., Kaji, T., Sato, H., Okuyama, T., Rumi, K.M.A., Adachi, K., Watanabe, M., Kinoshita, Y. (2001) T cell-mediated cytotoxicity via Fas/Fas ligand signaling in Helicobacter pylori-infected gastric corpus. Helicobacter 6, 283293.
  • [33]
    Mannick, E.E., Bravo, L.E., Zarama, G., Realpe, J.L., Zhang, X-J., Ruiz, B., Fontham, E.T.H., Mera, R., Miller, M.J.S., Correa, P. (1996) Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Research 56, 32383243.
  • [34]
    Tarkkanen, J., Kosunen, T.U., Saksela, E. (1993) Contact of lymphocytes with Helicobacter pylori augments natural killer cell activity and induces production of gamma interferon. Infect. Immun. 61, 30123016.
  • [35]
    Marchant, A., Bruyns, C., Vandenabeele, P., Ducarme, M., Gérard, C., Delvaux, A., De Groote, D., Abramowicz, D., Velu, T., Goldman, M. (1994) Interleukin-10 controls interferon-γ and tumor necrosis factor production during experimental endotoxemia. Eur. J. Immunol. 24, 11671171.