Expression of Toll-Like Receptors 2 and 3 on Esophageal Epithelial Cell Lines and on Eosinophils During Esophagitis

Mulder, Daniel J.; Lobo, David; Mak, Nanette; Justinich, Christopher J.

doi:10.1007/s10620-011-1907-4

Cited by 22 publications

(19 citation statements)

References 41 publications

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“…IL8 expression and secretion, which were used as a readout for the induction of an inflammatory response, were increased following TLR2 stimulation in BE (BAR-T) cells. Interestingly, IL8 secretion had previously been found to be induced in esophageal squamous cell carcinoma cell lines (TE-1 and TE-7) upon TLR2 activation, which was not shown in SQ cells (primary squamous epithelium cells, EPC2 and EPC2-hTERT) [29,39].…”

Section: Discussionmentioning

confidence: 92%

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Verbeek

Siersema

Vleggaar

et al. 2016

JGLD

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Background & Aims: Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett’s esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett’s esophagus epithelium cell line. Methods: TLR2 expression in normal squamous esophagus, reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma biopsies was assessed with Q-RT-PCR, in situ hybridization and immunohistochemistry. Barrett’s esophagus epithelium cells (BAR-T) were incubated with acid and bile salts in the presence or absence of the TLR2 agonist Pam3CSK4 for a period up to 4 weeks. Morphological changes were assessed with electron microscopy, while Q-RT-PCR was used to determine the expression of lysosomal enzymes (Cathepsin B and C) and factors involved in endocytosis (LAMP-1 and M6PR) and autophagy (LC3 and Rab7). Results: TLR2 was expressed in normal squamous esophagus, reflux esophagitis, Barrett’s esophagus but was most prominent in esophageal adenocarcinoma. Long-term TLR2 activation in acid and bile salts exposed BAR-T cells resulted in more and larger lysosomes, more mitochondria and increased expression of LAMP-1, M6PR, Cathepsin B and C when compared to BAR-T cells incubated with acid and bile salts but no TLR2 agonist. Factors associated with autophagy (LC3 and Rab7) expression remained largely unchanged. Conclusion: Activation of TLR2 in acid and bile salts exposed Barrett epithelium cells resulted in an increased number of mitochondria and lysosomes and increased expression of lysosomal enzymes and factors involved in endocytosis. Abbreviations: BE: Barrett’s esophagus; DCA: deoxycholic acid; EAC: esophageal adenocarcinoma; GCA: glycocholic acid; IL8: interleukin 8; IHC: immunohistochemistry; ISH: in situ hybridization; LAMP-1: lysosomal-associated membrane protein-1; LC3: microtubule-associated protein 1A/1B-light chain 3; M6PR: mannose-6-phosphate receptor; NF-κB: Nuclear Factor–κB; PPIs: proton pump inhibitors; Q-RT-PCR: Quantitative reverse transcriptase polymerase chain reaction; RE: reflux esophagitis; SQ: normal squamous esophagus; TCDCA: taurochenodeoxycholic acid; TLR: Toll-like receptor; TNFα: tumor necrosis factor α.

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Section: Discussionmentioning

confidence: 92%

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Verbeek

Siersema

Vleggaar

et al. 2016

JGLD

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“…This may be responsible for enhanced permeability of the epithelium to local food and environmental allergens, leading to increased access of antigens and activation of epithelial cell to produce cytokines and chemokines that ultimately induce the Th2 inflammation [76]. It is well established that the esophageal epithelium is more than a physical barrier, as it expresses Toll-like receptors [77,78] and produces pro-inflammatory cytokines in response to both pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) [77].…”

Section: Epithelial Dysfunctionmentioning

confidence: 99%

Eosinophilic Esophagitis and Gastroenteritis

Cianferoni

Spergel

2015

Curr Allergy Asthma Rep

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Eosinophilic gastrointestinal disease (EGID) can be classified as eosinophilic esophagitis (EoE) when the eosinophilia is limited to the esophagus or as eosinophilic gastritis (EG) if it is limited to the gastric tract, eosinophilic colitis (EC) if it is limited to the colon, and eosinophilic gastroenteritis (EGE) if the eosinophilia involves one or more parts of the gastrointestinal tract. EoE is by far the most common EGID. It is a well-defined chronic atopic disease due to a T helper type 2 (Th2) inflammation triggered often by food allergens. EoE diagnosis is done if an esophageal biopsy shows at least 15 eosinophils per high power field (eos/hpf). Globally accepted long-term therapies for EoE are the use of swallowed inhaled steroids or food antigen avoidance. The treatment of EoE is done not only to control symptoms but also to prevent complications such as esophageal stricture and food impaction. EGE cause non-specific gastrointestinal (GI) symptoms and are diagnosed if esophagogastroduodenoscopy (EGD)/colonoscopy show eosinophilia in one or more parts of the GI tract. They are rare diseases with an unclear pathogenesis, and they are poorly defined in terms of diagnostic criteria and treatment. Before initiating treatment of any EGE, it is imperative to conduct a differential diagnosis to exclude other causes of hypereosinophilia with GI localization. EGE are often poorly responsive to therapy and there is no commonly accepted long-term treatment. EG has many characteristics similar to EoE, including the fact that it is often due to a food allergen-driven Th2 inflammation; transcriptome analysis however shows that it is more a systemic disease and has a different gene signature than EoE. EC is a benign form of delayed food allergy in infant and is instead a difficult-to-treat severe inflammatory condition in older children and adults. EC in the latter groups can be a manifestation of drug allergy or autoimmune disease. Overall EGE, EC, and EG are rare and are a diagnosis of exclusion until more common causes of eosinophilia have been excluded.

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“…45 Primary human conjunctival ECs express TSLP mRNA and release TSLP in response to polyI:C. 43,44 Primary human oral ECs release TSLP in response to polyI:C. 57 Primary human esophagus ECs express increased TSLP mRNA levels in response to polyI:C 19 ; and human esophagus EC lines, in response to polyI:C and zymosan (TLR2-TLR6 ligand). 58 The human colonic EC line Caco-2 expressed TSLP mRNA in response to polyI:C 15 and flagellin. 59 Primary human synovial fibroblasts release TSLP in response to polyI:C and LPS.…”

Section: Tlr Ligandsmentioning

confidence: 99%

TSLP Expression: Cellular Sources, Triggers, and Regulatory Mechanisms

Takai

2012

Allergology International

229

194

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Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine initially identified in the culture supernatant of a thymic stromal cell line. Highly expressed in the epidermis in skin lesions of atopic dermatitis patients, TSLP was subsequently found to be a critical factor linking responses at interfaces between the body and environment (skin, airway, gut, ocular tissues, and so on) to Th2 responses. Recent studies have revealed that various cell types other than epithelial cells and epidermal keratinocytes (such as mast cells, airway smooth muscle cells, fibroblasts, dendritic cells, trophoblasts, and cancer or cancer-associated cells) also express TSLP. Environmental factors such as Toll-like receptor ligands, a Nod2 ligand, viruses, microbes, allergen sources, helminths, diesel exhaust, cigarette smoke, and chemicals trigger TSLP production. Proinflammatory cytokines, Th2-related cytokines, and IgE also induce or enhance TSLP production, indicating cycles of amplification. Skin barrier injury, increased epidermal endogenous protease activity, and less epidermal Notch signaling, all of which have been reported in atopic dermatitis, and keratinocyte-specific loss of retinoid X receptors and treatment of skin with agonists for vitamin D receptor in mice induce TSLP production, Th2 response, or atopic dermatitis-like inflammation. The transcription factors NF-κB and AP-1, nuclear receptors, single nucleotide polymorphisms, microRNAs, and the peptidyl-proryl isomerase Pin1 regulate TSLP mRNA expression transcriptionally or posttranscriptionally. This review focuses on events upstream of TSLP production, which is critical in allergic diseases and important in other TSLP-related disorders i.e. production sites, cellular sources, environmental and endogenous triggers and regulatory factors, and regulatory mechanisms of gene expression.

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Expression of Toll-Like Receptors 2 and 3 on Esophageal Epithelial Cell Lines and on Eosinophils During Esophagitis

Abstract: TLR2 and TLR3 expression on cultured esophageal epithelial cells differs from TLR2 and TLR3 expression in esophageal biopsies, which is limited to immune cells during esophagitis.

Cited by 22 publications

References 41 publications

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Eosinophilic Esophagitis and Gastroenteritis

TSLP Expression: Cellular Sources, Triggers, and Regulatory Mechanisms

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