학술논문
Contribution of [CD3.sup.+][CD8.sup.-] and [CD3.sup.+][CD8.sup.+] T Cells to TNF-[alpha] Overexpression in Crohn Disease-Associated Perianal Fistulas and Induction of Epithelial-Mesenchymal Transition in HT-29 Cells
ORIGINAL RESEARCH ARTICLE--BASIC SCIENCE
ORIGINAL RESEARCH ARTICLE--BASIC SCIENCE
Document Type
Academic Journal
Author
Bruckner, Ramona S.; Spalinger, Marianne R.; Barnhoorn, Marieke C.; Feakins, Roger; Fuerst, Alois; Jehle, Ekkehard C.; Rickenbacher, Andreas; Turina, Matthias; Niechcial, Anna; Lang, Silvia; Hawinkels, Lukas J.A.C.; van der Meulen-de Jong, Andrea E.; Verspaget, Hein W.; Rogler, Gerhard; Scharl, Michael
Source
Inflammatory Bowel Diseases. April 2021, Vol. 27 Issue 4, p538, 12 p.
Subject
Language
English
ISSN
1078-0998
Abstract
INTRODUCTION Fistulas represent a frequent and severe complication in up to 50% of patients with Crohn disease (CD) during their disease course. (1,2) Current knowledge about fistula pathogenesis is scarce, [...]
Background: Fistulas represent a frequent and severe complication in patients with Crohn disease (CD). Tumor necrosis factor-alpha (TNF-[alpha]), transforming growth factor-beta, and interleukin (IL)-13 are known to trigger epithelial-mesenchymal transition (EMT), promoting fistula formation. Here, we investigated the role of T-lymphocytes (T cells) in fistula pathogenesis. Methods: [CD3.sup.+][CD8.sup.-], [CD3.sup.+][CD8.sup.+], or [CD45.sup.+][CD3.sup.-] cells from healthy volunteers, patients with CD, and patients with CD with perianal fistula were co-cultured with HT-29 cells. The EMT, cytokine production, and mRNA expression were analyzed. Perianal CD fistula specimens were immunohistochemically stained for cytokines and their receptors. The effect of cytokines on EMT induction was investigated using an EMT spheroid model. Results: Patients with CD with fistula revealed more [CD3.sup.+] [CD8.sup.-] and less [CD3.sup.+][CD8.sup.+] T cells in blood than healthy control patients and patients with CD without fistula. In perianal fistula specimens, [CD4.sup.+] cells--and to a lesser extent [CD8.sup.+] cells--were highly present around fistula tracts. When co-cultured with HT-29 cells, both cell subsets promoted EMT-related gene expression and TNF-[alpha] production in a time-dependent manner. The [CD3.sup.+][CD8.sup.-] T cells from patients with CD with fistula also produced higher amounts of IL-13 than cells from healthy control patients or patients with CD without a fistula. We found that IL-22 and [IL-22R.sub.[alpha]1] were highly expressed in perianal CD fistula specimens and that IL-22 cotreatment potentiated TNF-[alpha]-induced EMT in HT-29 spheroids. Conclusions: Our data indicate that both [CD3.sup.+][CD8.sup.-] and [CD3.sup.+][CD8.sup.+] T cells play an important role in the pathogenesis of perianal CD fistulas by the secretion of TNF-[alpha]. Our data support clinical evidence indicating that anti-TNF-[alpha] therapy is effective in fistula treatment and identify IL-13 and IL-22 as possible novel therapeutic targets for fistula therapy. Key Words: Crohn disease, fistulas, T-lymphocytes, tumor necrosis factor-alpha
Background: Fistulas represent a frequent and severe complication in patients with Crohn disease (CD). Tumor necrosis factor-alpha (TNF-[alpha]), transforming growth factor-beta, and interleukin (IL)-13 are known to trigger epithelial-mesenchymal transition (EMT), promoting fistula formation. Here, we investigated the role of T-lymphocytes (T cells) in fistula pathogenesis. Methods: [CD3.sup.+][CD8.sup.-], [CD3.sup.+][CD8.sup.+], or [CD45.sup.+][CD3.sup.-] cells from healthy volunteers, patients with CD, and patients with CD with perianal fistula were co-cultured with HT-29 cells. The EMT, cytokine production, and mRNA expression were analyzed. Perianal CD fistula specimens were immunohistochemically stained for cytokines and their receptors. The effect of cytokines on EMT induction was investigated using an EMT spheroid model. Results: Patients with CD with fistula revealed more [CD3.sup.+] [CD8.sup.-] and less [CD3.sup.+][CD8.sup.+] T cells in blood than healthy control patients and patients with CD without fistula. In perianal fistula specimens, [CD4.sup.+] cells--and to a lesser extent [CD8.sup.+] cells--were highly present around fistula tracts. When co-cultured with HT-29 cells, both cell subsets promoted EMT-related gene expression and TNF-[alpha] production in a time-dependent manner. The [CD3.sup.+][CD8.sup.-] T cells from patients with CD with fistula also produced higher amounts of IL-13 than cells from healthy control patients or patients with CD without a fistula. We found that IL-22 and [IL-22R.sub.[alpha]1] were highly expressed in perianal CD fistula specimens and that IL-22 cotreatment potentiated TNF-[alpha]-induced EMT in HT-29 spheroids. Conclusions: Our data indicate that both [CD3.sup.+][CD8.sup.-] and [CD3.sup.+][CD8.sup.+] T cells play an important role in the pathogenesis of perianal CD fistulas by the secretion of TNF-[alpha]. Our data support clinical evidence indicating that anti-TNF-[alpha] therapy is effective in fistula treatment and identify IL-13 and IL-22 as possible novel therapeutic targets for fistula therapy. Key Words: Crohn disease, fistulas, T-lymphocytes, tumor necrosis factor-alpha