Abstract | Background: Anti- tumor necrosis factor (TNF) therapy appears to be effective in the treatment of Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract. However, the mechanisms involved are not completely understood. Methods: Fifty-seven active CD patients were enrolled, and cytokine profiles in colonic biopsies of patients with active CD receiving anti-TNF monoclonal antibody (mAb) ( infliximab [IFX]) treatment were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Colonic biopsies of active CD patients and healthy donors were cultured with IFX in vitro, and cytokine profiles were measured by qRT-PCR. Peripheral blood (PB)-CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAbs in the presence of human immunoglobin (HIg), IFX, recombinant human TNF-α converting enzyme (rhTACE), and aryl hydrocarbon receptor (AhR) inhibitor (CH-223191), respectively, to determine interleukin (IL)-22 expression by CD4+ T cells. Caco2 cells were also utilized to study their potential role in modulating epithelial cell barrier repairs in vitro. Results: IFX therapy markedly upregulated IL-22 mRNA expression in the gut mucosa of CD patients. In vitro treatment with IFX greatly promoted CD CD4+ T cells to express IL-22, which was inhibited by rhTACE, indicating that reverse signaling through binding to membrane-bound TNF mediates anti-TNF-induced IL-22 expression of CD CD4+ T cells. However, blockade of AhR markedly inhibited anti-TNF-induced IL-22+CD4+ T (Th22) cell differentiation in CD patients. Moreover, treatment with IL-22 induced intestinal epithelial cell expression of tight junction proteins (eg, claudin1 and ZO-1) and facilitated transepithelial resistance, indicating that IL-22 protects intestinal mucosa from inflammation via maintenance of epithelial barrier integrity. Conclusions: Our results uncover a novel mechanism whereby anti-TNF therapy upregulates IL-22 production in CD patients through promoting Th22 cell differentiation and contributes to intestinal epithelial barrier repairs.
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Authors | Leilei Fang, Zhi Pang, Weigang Shu, Wei Wu, Mingming Sun, Yingzi Cong, Zhanju Liu |
Journal | Inflammatory bowel diseases
(Inflamm Bowel Dis)
Vol. 24
Issue 8
Pg. 1733-1744
(07 12 2018)
ISSN: 1536-4844 [Electronic] England |
PMID | 29718341
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Interleukins
- Tumor Necrosis Factor-alpha
- Infliximab
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Topics |
- Adolescent
- Adult
- Antibodies, Monoclonal
(therapeutic use)
- CD4-Positive T-Lymphocytes
(immunology, metabolism)
- Caco-2 Cells
- Cell Proliferation
(drug effects)
- Crohn Disease
(drug therapy, genetics, metabolism, pathology)
- Female
- Humans
- Infliximab
- Interleukins
(biosynthesis, genetics)
- Intestinal Mucosa
(pathology)
- Male
- Th17 Cells
(drug effects, immunology)
- Tumor Necrosis Factor-alpha
(antagonists & inhibitors)
- Young Adult
- Interleukin-22
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