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. 2000 Jul;47(1):79–87. doi: 10.1136/gut.47.1.79

Non-pathogenic bacteria elicit a differential cytokine response by intestinal epithelial cell/leucocyte co-cultures

D Haller 1, C Bode 1, W Hammes 1, A Pfeifer 1, E Schiffrin 1, S Blum 1
PMCID: PMC1727962  PMID: 10861268

Abstract

BACKGROUND AND AIM—Intestinal epithelial cells (IEC) are thought to participate in the mucosal defence against bacteria and in the regulation of mucosal tissue homeostasis. Reactivity of IEC to bacterial signals may depend on interactions with immunocompetent cells. To address the question of whether non-pathogenic bacteria modify the immune response of the intestinal epithelium, we co-cultivated enterocyte-like CaCO-2 cells with human blood leucocytes in separate compartments of transwell cultures.
METHODS—CaCO-2/PBMC co-cultures were stimulated with non-pathogenic bacteria and enteropathogenic Escherichia coli. Expression of tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-8, monocyte chemoattracting protein 1 (MCP-1), and IL-10 was studied by enzyme linked immunosorbent assays (cytokine secretion) and by semiquantitative reverse transcription-polymerase chain reaction.
RESULTS—Challenge of CaCO-2 cells with non-pathogenic E coli and Lactobacillus sakei induced expression of IL-8, MCP-1, IL-1β, and TNF-α mRNA in the presence of underlying leucocytes. Leucocyte sensitised CaCO-2 cells produced TNF-α and IL-1β whereas IL-10 was exclusively secreted by human peripheral blood mononuclear cells. CaCO-2 cells alone remained hyporesponsive to the bacterial challenge. Lactobacillus johnsonii, an intestinal isolate, showed reduced potential to induce proinflammatory cytokines but increased transforming growth factor beta mRNA in leucocyte sensitised CaCO-2 cells. TNF-α was identified as one of the early mediators involved in cellular cross talk. In the presence of leucocytes, discriminative activation of CaCO-2 cells was observed between enteropathogenic E coli and non-pathogenic bacteria.
CONCLUSION—The differential recognition of non-pathogenic bacteria by CaCO-2 cells required the presence of underlying leucocytes. These results strengthen the hypothesis that bacterial signalling at the mucosal surface is dependent on a network of cellular interactions.


Keywords: CaCO-2 cells; leucocytes; enteropathogenic E coli; Lactobacilli; tumour necrosis factor; interleukin 1β; interleukin 10; chemokines

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Figure 1  .

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Differential chemokine expression in CaCO-2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to determine monocyte chemoattracting protein 1 (MCP-1) (A) and interleukin (IL)-8 (B) mRNA expression in CaCO-2 cells on stimulation of CaCO-2/leucocyte co-cultures or CaCO-2 cells alone with non-pathogenic E coli, L johnsonii, and L sakei (16 hours, 106 and 107 cfu/ml), respectively. Lipopolysaccharide (LPS, 1 µg/ml), IL-1β (10 ng/ml) and culture medium (no treatment) were used as controls. Results represent one of three independent experiments.

Figure 2  .

Figure 2  

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Bacteria induced tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1β response by CaCO-2/leucocyte co-cultures. Stimulation of CaCO-2/leucocyte co-cultures with non-pathogenic E coli, L johnsonii, and L sakei (16 hours, 107 cfu/ml). Secretion of TNF-α (A) and IL-1β (B) into the basolateral compartment was determined (bar charts). Culture medium (no treatment) was used as a control. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to determine expression of TNF-α (A) and IL-1β (B) mRNA in leucocyte sensitised CaCO-2 cells. Data are mean (SD) of triplicate values and represent one of three independent experiments.

Figure 3  .

Figure 3  

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Polarised secretion of tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1β by leucocyte sensitised CaCO-2 cells. Stimulation of CaCO-2/leucocyte co-cultures or CaCO-2 cells alone with non-pathogenic E coli (107 cfu/ml). After 12 hours of incubation, CaCO-2 cells were transferred to fresh culture medium. After an additional 24 hours of incubation, secretion of TNF-α and IL-1β by leucocyte sensitised CaCO-2 cells was determined in the apical and basolateral compartments (transfer experiment). Controls (no treatment) did not induce cytokine secretion. Data are mean (SD) of triplicate values and represent one of three independent experiments.

Figure 4  .

Figure 4  

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Differential expression of transforming growth factor beta (TGF-β) mRNA in CaCO-2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to determine TGF-β mRNA expression in CaCO-2 cells on stimulation of CaCO-2/leucocyte co-cultures or CaCO-2 cells alone with non-pathogenic E coli, L johnsonii, and L sakei (16 hours, 106 and 107 cfu/ml), respectively. Lipopolysaccharide (LPS, 1 µg/ml), interleukin (IL)-1β (10 ng/ml), and culture medium (no treatment) were used as controls. Results represent one of three independent experiments.

Figure 5  .

Figure 5  

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Induction of interleukin (IL)-10 response by CaCO-2/leucocyte co-cultures. Secretion of IL-10 was determined in the basolateral compartment on stimulation of CaCO-2/leucocyte co-cultures with non-pathogenic E coli, L johnsonii, and L sakei (16 hours, 107 cfu/ml), respectively (bar charts). Culture medium (no treatment) was used as a control. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to determine IL-10 mRNA expression in conditioned PBMC. Data are mean (SD) of triplicate values and represent one of three independent experiments.

Figure 6  .

Figure 6  

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Neutralisation of tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1β in CaCO-2/leucocyte co-cultures. CaCO-2/ leucocyte co-cultures were stimulated with non-pathogenic E coli (16 hours, 107 cfu/ml) in the presence of neutralising anti-TNF-α monoclonal antibody (mAb) or IL-1β mAb (10 µg/ml). A positive control was performed in the absence of neutralising antibodies. Challenge of CaCO-2/leucocyte co-cultures with culture medium alone was used as a negative control. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to determine TNF-α (A) and IL-8 (B) mRNA expression in CaCO-2 cells. Results represent one of three independent experiments.

Figure 7  .

Figure 7  

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Differential induction of tumour necrosis factor alpha (TNF-α) mRNA by leucocyte sensitised CaCO-2 cells stimulated with enteropathogenic E coli and non-pathogenic bacteria. Stimulation of CaCO-2/leucocyte co-cultures with live or heat killed (95°C/30 minutes) EPEC strain E2348/69 and its eaeA deletion mutant CVD206, and non-pathogenic E coli, L johnsonii, and L sakei (107 cfu/ml) for four hours in the absence of gentamycin (150 µg/ml). Culture medium (no treatment) was used as a control. Expression of TNF-α mRNA in CaCO-2 cells was determined after 6, 16, and 36 hours of incubation by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Results represent one of three independent experiments.

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