Reduced Human α-defensin 6 in Noninflamed Jejunal Tissue of Patients with Crohn’s Disease

Hayashi, Ryohei; Tsuchiya, Kiichiro; Fukushima, Kunihiro; Horita, Nobukatsu; Hibiya, Shuji; Kitagaki, Keisuke; Negi, Mariko; Itoh, Eiichi; Akashi, Takumi; Eishi, Yoshinobu; Okada, Eriko; Araki, Akihiro; Ohtsuka, Kazuo; Fukuda, Shinji; Ohno, Hiroshi; Okamoto, Ryuichi; Nakamura, Toshio; Tanaka, Shinji; Chayama, Kazuaki; Watanabe, Mamoru

doi:10.1097/mib.0000000000000707

Cited by 17 publications

(17 citation statements)

References 26 publications

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“…Our studies of HD5 as a candidate biomarker for CC suggest it could be a diagnostic signature to efficiently distinguish CC from UC. Newly published data shows that patients with small bowel Crohn's disease (Crohn’s ileitis) are characterized with a deficiency of HD5, as shown by a reduced expression and secretion of the Paneth cell HD5, a fundamental feature of Crohn’s ileitis [ 48 – 51 ]. Our data, in CC, the reverse is true.…”

Section: Discussionmentioning

confidence: 99%

Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease

et al. 2017

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Inability to distinguish Crohn's colitis from ulcerative colitis leads to the diagnosis of indeterminate colitis. This greatly effects medical and surgical care of the patient because treatments for the two diseases vary. Approximately 30 percent of inflammatory bowel disease patients cannot be accurately diagnosed, increasing their risk of inappropriate treatment. We sought to determine whether transcriptomic patterns could be used to develop diagnostic biomarker(s) to delineate inflammatory bowel disease more accurately. Four patients groups were assessed via whole-transcriptome microarray, qPCR, Western blot, and immunohistochemistry for differential expression of Human α-Defensin-5. In addition, immunohistochemistry for Paneth cells and Lysozyme, a Paneth cell marker, was also performed. Aberrant expression of Human α-Defensin-5 levels using transcript, Western blot, and immunohistochemistry staining levels was significantly upregulated in Crohn's colitis, p< 0.0001. Among patients with indeterminate colitis, Human α-Defensin-5 is a reliable differentiator with a positive predictive value of 96 percent. We also observed abundant ectopic crypt Paneth cells in all colectomy tissue samples of Crohn's colitis patients. In a retrospective study, we show that Human α-Defensin-5 could be used in indeterminate colitis patients to determine if they have either ulcerative colitis (low levels of Human α-Defensin-5) or Crohn's colitis (high levels of Human α-Defensin-5). Twenty of 67 patients (30 percent) who underwent restorative proctocolectomy for definitive ulcerative colitis were clinically changed to de novo Crohn's disease. These patients were profiled by Human α-Defensin-5 immunohistochemistry. All patients tested strongly positive. In addition, we observed by both hematoxylin and eosin and Lysozyme staining, a large number of ectopic Paneth cells in the colonic crypt of Crohn's colitis patient samples. Our experiments are the first to show that Human α-Defensin-5 is a potential candidate biomarker to molecularly differentiate Crohn's colitis from ulcerative colitis, to our knowledge. These data give us both a potential diagnostic marker in Human α-Defensin-5 and insight to develop future mechanistic studies to better understand crypt biology in Crohn's colitis.

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Section: Discussionmentioning

confidence: 99%

Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease

et al. 2017

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“…The reason for different observations between the previous and current studies remains unclear, but our findings indicate that LL-37 is induced in the inflamed mucosa of IBD patients and suggest that LL-37 may act as one of the protective factors against microbial invasion which aggravate gut inflammation. In contrast to reduced expression of HD5 and HD6 in the small intestine in patients with ileal CD [31,32], antimicrobial activity in the colon might be enhanced through increased expression of LL-37 in colonic SEMFs.…”

Section: Discussionmentioning

confidence: 91%

“…Patients with CD of the ileum are characterized by reduced constitutive expression of HD5 and HD 6 and, accordingly, compromised anti-microbial barrier function [31,32]. Epithelial cells have been reported to be a major expression site of LL-37 in various tissues [33].…”

Section: Discussionmentioning

confidence: 99%

Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease

Kusaka

Nishida

Takahashi

et al. 2017

Clinical and Experimental Immunology

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Summary Cathelicidin peptide LL-37 plays an important role in the early host response against invading pathogens via its broad-spectrum anti-microbial activity. In this study, we investigated LL-37 expression in the inflamed mucosa of inflammatory bowel disease (IBD) patients. Furthermore, the regulatory mechanism of LL-37 induction was investigated in human colonic subepithelial myofibroblasts (SEMFs). LL-37 mRNA expression and protein secretion were analysed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Intracellular signalling pathways were analysed using immunoblotting and specific small interference RNA (siRNA). The expression of LL-37 mRNA was increased significantly in the inflamed mucosa of ulcerative colitis and Crohn's disease. The Toll-like receptor (TLR)-3 ligand, polyinosinic-polycytidylic acid (poly(I:C), induced LL-37 mRNA expression and stimulated LL-37 secretion in colonic SEMFs. The transfection of siRNAs specific for intracellular signalling proteins [Toll/IL-1R domain-containing adaptor-inducing interferon (IFN) (TRIF), tumour necrosis factor receptor-associated factor (TRAF)6, transforming growth factor β-activated kinase (TAK)1] suppressed the poly(I:C)-induced LL-37 mRNA expression significantly. Poly(I:C)-induced phosphorylation of mitogen-activated protein kinases (MAPKs) and activated nuclear factor kappa B (NF-κB) and activating factor protein (AP)-1. siRNAs specific for NF-κB and c-Jun inhibited poly(I:C)-induced LL-37 mRNA expression. LL-37 suppressed lipopolysaccharide (LPS)-induced interleukin (IL)-6 and IL-8 expression significantly in colonic SEMFs. The expression of LL-37 was up-regulated in the inflamed mucosa of IBD patients. LL-37 was induced by TLR-3 stimulation and exhibited an anti-microbial effect via interaction with lipopolysaccharide (LPS).

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“…Induction of HD5 and HD6 gene expression in GC-exposed cervicovaginal epithelial cells contributes to GC-mediated enhanced HIV infectivity [31]. HD6 gene expression is upregulated by atonal homolog 1 and β-catenin in colon cancer cell lines, DLD1 and SW480 [32]. The TCF4 binding site and E-box site in the proximal promoter region are critical for HD6 gene expression.…”

Section: Overview Of Human Defensins and Their Regulationmentioning

confidence: 99%

Multifaceted immune functions of human defensins and underlying mechanisms

Fruitwala

El-Naccache

Chang

2019

Seminars in Cell & Developmental Biology

128

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Defensins have been long recognized as natural antimicrobial peptides, but they also possess diverse and versatile immune functions. Defensins can both induce inflammation and suppress inflammatory responses by acting on specific cells through distinct mechanisms. Defensins can also modulate the immune response by forming a complex with cellular molecules including proteins, nucleic acids, and carbohydrates. The mechanisms of defensin-mediated immune modulation appear to be cell-type and context specific. Because the levels of human defensins are often altered in response to infection or disease states, suggesting their clinical relevance, this review summarizes the complex immune functions of human defensins and their underlying mechanisms of action, which have implications for the development of new therapeutics.

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Reduced Human α-defensin 6 in Noninflamed Jejunal Tissue of Patients with Crohn’s Disease

Abstract: HD6 expression was found to be regulated by cooperation between Atoh1 and β-catenin within the HD6 promoter region. Downregulation of HD6 in noninflamed mucosa may contribute to mucosal barrier dysfunction of patients with CD.

Cited by 17 publications

References 26 publications

Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease

Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease

Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease

Multifaceted immune functions of human defensins and underlying mechanisms

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