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The role of interleukin 17 in Crohn's disease-associated intestinal fibrosis.

Biancheri P, Pender SL, Ammoscato F, Giuffrida P, Sampietro G, Ardizzone S, Ghanbari A, Curciarello R, Pasini A, Monteleone G, Corazza GR, Macdonald TT, Di Sabatino A - Fibrogenesis Tissue Repair (2013)

Bottom Line: IL-17A was significantly overexpressed in strictured compared with non-strictured CD tissues, whereas no significant difference was found in the expression of IL-17E or IL-17A and IL-17E receptors (IL-17RC and IL-17RB, respectively) in strictured and non-strictured CD areas.Strictured CD explants released significantly higher amounts of IL-17A than non-strictured explants, whereas no difference was found as for IL-17E, IL-6, or tumor necrosis factor-α production.Our results suggest that IL-17A, but not IL-17E, is pro-fibrotic in CD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK. t.t.macdonald@qmul.ac.uk.

ABSTRACT

Background: Interleukin (IL)-17A and IL-17E (also known as IL-25) have been implicated in fibrosis in various tissues. However, the role of these cytokines in the development of intestinal strictures in Crohn's disease (CD) has not been explored. We investigated the levels of IL-17A and IL-17E and their receptors in CD strictured and non-strictured gut, and the effects of IL-17A and IL-17E on CD myofibroblasts.

Results: IL-17A was significantly overexpressed in strictured compared with non-strictured CD tissues, whereas no significant difference was found in the expression of IL-17E or IL-17A and IL-17E receptors (IL-17RC and IL-17RB, respectively) in strictured and non-strictured CD areas. Strictured CD explants released significantly higher amounts of IL-17A than non-strictured explants, whereas no difference was found as for IL-17E, IL-6, or tumor necrosis factor-α production. IL-17A, but not IL-17E, significantly inhibited myofibroblast migration, and also significantly upregulated matrix metalloproteinase (MMP)-3, MMP-12, tissue inhibitor of metalloproteinase-1 and collagen production by myofibroblasts from strictured CD tissues.

Conclusions: Our results suggest that IL-17A, but not IL-17E, is pro-fibrotic in CD. Further studies are needed to clarify whether the therapeutic blockade of IL-17A through the anti-IL-17A monoclonal antibody secukinumab is able to counteract the fibrogenic process in CD.

No MeSH data available.


Related in: MedlinePlus

Effect of interleukin (IL)-17A and IL-17E on the production of matrix metalloproteinase (MMP)-3, MMP-12, and tissue inhibitor of metalloproteinase (TIMP)-1 by intestinal myofibroblasts. (A) MMP-3, (B) MMP-12, and (C) (TIMP-1 in culture supernatants of myofibroblasts isolated from uninflamed areas of strictured (Strict uninfl) and non-strictured (Non-strict uninfl) gut of six patients with fibrostenosing Crohn’s disease (CD) and from normal gut of six healthy control (HC) subjects, cultured for 24 hours with medium alone or recombinant human (rh) tumor necrosis factor (TNF)-α, or rhIL-17A, or rhIL-17E. Blots are representative of experiments performed in all patients with CD and HC subjects. Lower panels show densitometry of western blots. Values are mean ± SEM. *P<0.05 versus myofibroblasts from the same study group cultured with medium alone. §P<0.05 versus Non-strict uninfl CD and HC myofibroblasts cultured under the same conditions.
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Figure 5: Effect of interleukin (IL)-17A and IL-17E on the production of matrix metalloproteinase (MMP)-3, MMP-12, and tissue inhibitor of metalloproteinase (TIMP)-1 by intestinal myofibroblasts. (A) MMP-3, (B) MMP-12, and (C) (TIMP-1 in culture supernatants of myofibroblasts isolated from uninflamed areas of strictured (Strict uninfl) and non-strictured (Non-strict uninfl) gut of six patients with fibrostenosing Crohn’s disease (CD) and from normal gut of six healthy control (HC) subjects, cultured for 24 hours with medium alone or recombinant human (rh) tumor necrosis factor (TNF)-α, or rhIL-17A, or rhIL-17E. Blots are representative of experiments performed in all patients with CD and HC subjects. Lower panels show densitometry of western blots. Values are mean ± SEM. *P<0.05 versus myofibroblasts from the same study group cultured with medium alone. §P<0.05 versus Non-strict uninfl CD and HC myofibroblasts cultured under the same conditions.

Mentions: Matrix metalloproteinase (MMP)-3, MMP-12, and TIMP-1 production was evaluated by immunoblotting in culture supernatants of myofibroblasts isolated from uninflamed areas of strictured or non-strictured gut of six patients with fibrostenosing CD, and from normal gut of six control subjects, and subsequently stimulated in vitro with recombinant human (rh)TNF-α, rhIL-17A, or rhIL-17E. rhIL-17A and rhIL-17E induced a significant (P<0.05) increase in both MMP-3 and MMP-12 production by myofibroblasts from strictured and non-strictured areas of patients with CD and from normal gut of control subjects (Figure 5A,B). rhTNF-α induced a significant (P<0.05) increase in both MMP-3 and MMP-12 production compared with control (myofibroblasts from the same group of patients cultured with medium alone). No significant difference in MMP-3 or MMP-12 production was found between rhTNF-α, rhIL-17A, and rhIL-17E stimulation in the three conditions studied. Myofibroblasts from CD strictured areas showed a significantly (P<0.05) lower spontaneous release of MMP-12 than myofibroblasts from CD non-strictured areas or control gut. Myofibroblast stimulation with rhIL-17A induced a significant (P<0.05) increase in TIMP-1 production compared with unstimulated cells from the same group of patients (Figure 5C). rhIL-17E did not induce any significant change in TIMP-1 production compared with myofibroblasts from the same group of patients cultured with medium alone. rhTNF-α induced a significant (P<0.05) increase in TIMP-1 production compared with myofibroblasts from the same group of patients cultured with medium alone. No significant difference in TIMP-1 production was found between rhTNF-α and rhIL-17A stimulation in all the three conditions studied.


The role of interleukin 17 in Crohn's disease-associated intestinal fibrosis.

Biancheri P, Pender SL, Ammoscato F, Giuffrida P, Sampietro G, Ardizzone S, Ghanbari A, Curciarello R, Pasini A, Monteleone G, Corazza GR, Macdonald TT, Di Sabatino A - Fibrogenesis Tissue Repair (2013)

Effect of interleukin (IL)-17A and IL-17E on the production of matrix metalloproteinase (MMP)-3, MMP-12, and tissue inhibitor of metalloproteinase (TIMP)-1 by intestinal myofibroblasts. (A) MMP-3, (B) MMP-12, and (C) (TIMP-1 in culture supernatants of myofibroblasts isolated from uninflamed areas of strictured (Strict uninfl) and non-strictured (Non-strict uninfl) gut of six patients with fibrostenosing Crohn’s disease (CD) and from normal gut of six healthy control (HC) subjects, cultured for 24 hours with medium alone or recombinant human (rh) tumor necrosis factor (TNF)-α, or rhIL-17A, or rhIL-17E. Blots are representative of experiments performed in all patients with CD and HC subjects. Lower panels show densitometry of western blots. Values are mean ± SEM. *P<0.05 versus myofibroblasts from the same study group cultured with medium alone. §P<0.05 versus Non-strict uninfl CD and HC myofibroblasts cultured under the same conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 5: Effect of interleukin (IL)-17A and IL-17E on the production of matrix metalloproteinase (MMP)-3, MMP-12, and tissue inhibitor of metalloproteinase (TIMP)-1 by intestinal myofibroblasts. (A) MMP-3, (B) MMP-12, and (C) (TIMP-1 in culture supernatants of myofibroblasts isolated from uninflamed areas of strictured (Strict uninfl) and non-strictured (Non-strict uninfl) gut of six patients with fibrostenosing Crohn’s disease (CD) and from normal gut of six healthy control (HC) subjects, cultured for 24 hours with medium alone or recombinant human (rh) tumor necrosis factor (TNF)-α, or rhIL-17A, or rhIL-17E. Blots are representative of experiments performed in all patients with CD and HC subjects. Lower panels show densitometry of western blots. Values are mean ± SEM. *P<0.05 versus myofibroblasts from the same study group cultured with medium alone. §P<0.05 versus Non-strict uninfl CD and HC myofibroblasts cultured under the same conditions.
Mentions: Matrix metalloproteinase (MMP)-3, MMP-12, and TIMP-1 production was evaluated by immunoblotting in culture supernatants of myofibroblasts isolated from uninflamed areas of strictured or non-strictured gut of six patients with fibrostenosing CD, and from normal gut of six control subjects, and subsequently stimulated in vitro with recombinant human (rh)TNF-α, rhIL-17A, or rhIL-17E. rhIL-17A and rhIL-17E induced a significant (P<0.05) increase in both MMP-3 and MMP-12 production by myofibroblasts from strictured and non-strictured areas of patients with CD and from normal gut of control subjects (Figure 5A,B). rhTNF-α induced a significant (P<0.05) increase in both MMP-3 and MMP-12 production compared with control (myofibroblasts from the same group of patients cultured with medium alone). No significant difference in MMP-3 or MMP-12 production was found between rhTNF-α, rhIL-17A, and rhIL-17E stimulation in the three conditions studied. Myofibroblasts from CD strictured areas showed a significantly (P<0.05) lower spontaneous release of MMP-12 than myofibroblasts from CD non-strictured areas or control gut. Myofibroblast stimulation with rhIL-17A induced a significant (P<0.05) increase in TIMP-1 production compared with unstimulated cells from the same group of patients (Figure 5C). rhIL-17E did not induce any significant change in TIMP-1 production compared with myofibroblasts from the same group of patients cultured with medium alone. rhTNF-α induced a significant (P<0.05) increase in TIMP-1 production compared with myofibroblasts from the same group of patients cultured with medium alone. No significant difference in TIMP-1 production was found between rhTNF-α and rhIL-17A stimulation in all the three conditions studied.

Bottom Line: IL-17A was significantly overexpressed in strictured compared with non-strictured CD tissues, whereas no significant difference was found in the expression of IL-17E or IL-17A and IL-17E receptors (IL-17RC and IL-17RB, respectively) in strictured and non-strictured CD areas.Strictured CD explants released significantly higher amounts of IL-17A than non-strictured explants, whereas no difference was found as for IL-17E, IL-6, or tumor necrosis factor-α production.Our results suggest that IL-17A, but not IL-17E, is pro-fibrotic in CD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK. t.t.macdonald@qmul.ac.uk.

ABSTRACT

Background: Interleukin (IL)-17A and IL-17E (also known as IL-25) have been implicated in fibrosis in various tissues. However, the role of these cytokines in the development of intestinal strictures in Crohn's disease (CD) has not been explored. We investigated the levels of IL-17A and IL-17E and their receptors in CD strictured and non-strictured gut, and the effects of IL-17A and IL-17E on CD myofibroblasts.

Results: IL-17A was significantly overexpressed in strictured compared with non-strictured CD tissues, whereas no significant difference was found in the expression of IL-17E or IL-17A and IL-17E receptors (IL-17RC and IL-17RB, respectively) in strictured and non-strictured CD areas. Strictured CD explants released significantly higher amounts of IL-17A than non-strictured explants, whereas no difference was found as for IL-17E, IL-6, or tumor necrosis factor-α production. IL-17A, but not IL-17E, significantly inhibited myofibroblast migration, and also significantly upregulated matrix metalloproteinase (MMP)-3, MMP-12, tissue inhibitor of metalloproteinase-1 and collagen production by myofibroblasts from strictured CD tissues.

Conclusions: Our results suggest that IL-17A, but not IL-17E, is pro-fibrotic in CD. Further studies are needed to clarify whether the therapeutic blockade of IL-17A through the anti-IL-17A monoclonal antibody secukinumab is able to counteract the fibrogenic process in CD.

No MeSH data available.


Related in: MedlinePlus