High Expression of the “A Disintegrin And Metalloprotease” 19 (ADAM19), a Sheddase for TNF-α in the Mucosa of Patients with Inflammatory Bowel Diseases

Franzè, Eleonora; Caruso, Roberta; Stolfi, Carmine; Sarra, Massimiliano; Cupi, Maria Laura; Ascolani, M.; Sedda, Silvia; Antenucci, Claudia; Ruffa, A.; Caprioli, Flavio; MacDonald, Thomas T.; Pallone, Francesco; Monteleone, Giovanni

doi:10.1097/mib.0b013e31828028e8

Cited by 23 publications

(22 citation statements)

References 44 publications

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“…Several studies have shown that TNF levels are upregulated in human IBD (10, 26). Having demonstrated TNF-regulation of NPY promoter in vitro , we next assessed if administration of TNF inhibitors can attenuate NPY expression during experimental colitis in mice.…”

Section: Resultsmentioning

confidence: 99%

Tumor Necrosis Factor–Neuropeptide Y Cross Talk Regulates Inflammation, Epithelial Barrier Functions, and Colonic Motility

Chandrasekharan

Jeppsson

Pienkowski

et al. 2013

Inflammatory Bowel Diseases

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Background Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is up regulated in the enteric nervous system (ENS) during murine colitis, and that NPY knockout mice exhibit reduced inflammation. Here we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main pro-inflammatory cytokine. Methods Utilizing primary enteric neurons and colon explant cultures from WT and NPY knockout (NPY−/−) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, utilizing the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). Results We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY−/− mice produced less TNF compared to WT. Further, TNF activated NPY promoter in enteric neurons via phospho-c-jun. NPY−/− mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability via phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF-inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared to etanercept. Conclusions We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF maybe a better therapeutic option than using anti-TNF antibodies.

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Section: Resultsmentioning

confidence: 99%

Tumor Necrosis Factor–Neuropeptide Y Cross Talk Regulates Inflammation, Epithelial Barrier Functions, and Colonic Motility

Chandrasekharan

Jeppsson

Pienkowski

et al. 2013

Inflammatory Bowel Diseases

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“…Previous studies have reported that Adam17 expression is upregulated in the intestinal mucosa of patients with IBD and in several mouse models of experimental colitis (99–103). Adam19 expression is also elevated in IBD (104). Apart from these reports, however, limited information exists on the role of these or other ADAMs in intestinal inflammation.…”

Section: Adams Intestinal Injury and Inflammatory Bowel Diseasementioning

confidence: 99%

ADAM Proteases and Gastrointestinal Function

Jones¹,

Rustagi

Dempsey³

2016

Annu. Rev. Physiol.

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A disintegrin and metalloproteinases (ADAMs) are a family of cell surface proteases that regulate diverse cellular functions, including cell adhesion, migration, cellular signaling, and proteolysis. Proteolytically active ADAMs are responsible for ectodomain shedding of membrane-associated proteins. ADAMs rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g., inflammation) and play a central role in coordinating intercellular communication within the local microenvironment. ADAM10 and ADAM17 are the most studied members of the ADAM family in the gastrointestinal tract. ADAMs regulate many cellular processes associated with intestinal development, cell fate specification, and the maintenance of intestinal stem cell/progenitor populations. Several signaling pathway molecules that undergo ectodomain shedding by ADAMs [e.g., ligands and receptors from epidermal growth factor receptor (EGFR)/ErbB and tumor necrosis factor α (TNFα) receptor (TNFR) families] help drive and control intestinal inflammation and injury/repair responses. Dysregulation of these processes through aberrant ADAM expression or sustained ADAM activity is linked to chronic inflammation, inflammation-associated cancer, and tumorigenesis.

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“…Treatment of TIMP3-deficient colonic epithelial cell line HT29-C1.16E with TIMP3, an inhibitor of ADAM17 activity, decreased TNF shedding and sensitized the cells to TNF-mediated epithelial hyperpermeability due to the downregulation of zonula occludens-1 proteins [64]. Other reports showed that IBD patients had also elevated mucosal expression of another TNF sheddase, metalloprotease ADAM19, localized mainly in epithelial cells [68], whereas a mouse study demonstrated that shedding of TNF can be mediated also by matrix metalloproteinase 13 (MMP13) [69]. …”

Section: Tnfmentioning

confidence: 99%

Tumour Necrosis Factor Superfamily Members in the Pathogenesis of Inflammatory Bowel Disease

Ślebioda

Kmieć

2014

Mediators of Inflammation

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Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract of unclear aetiology of which two major forms are Crohn's disease (CD) and ulcerative colitis (UC). CD and UC are immunologically distinct, although they both result from hyperactivation of proinflammatory pathways in intestines and disruption of intestinal epithelial barrier. Members of the tumour necrosis factor superfamily (TNFSF) are molecules of broad spectrum of activity, including direct disruption of intestinal epithelial barrier integrity and costimulation of proinflammatory functions of lymphocytes. Tumour necrosis factor (TNF) has a well-established pathological role in IBD which also serves as a target in IBD treatment. In this review we discuss the role of TNF and other TNFSF members, notably, TL1A, FasL, LIGHT, TRAIL, and TWEAK, in the pathogenesis of IBD.

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High Expression of the “A Disintegrin And Metalloprotease” 19 (ADAM19), a Sheddase for TNF-α in the Mucosa of Patients with Inflammatory Bowel Diseases

Abstract: These findings suggest the existence of a positive feedback mechanism involving cytokines and ADAM19 that can amplify cytokine production in IBD.

Cited by 23 publications

References 44 publications

Tumor Necrosis Factor–Neuropeptide Y Cross Talk Regulates Inflammation, Epithelial Barrier Functions, and Colonic Motility

Tumor Necrosis Factor–Neuropeptide Y Cross Talk Regulates Inflammation, Epithelial Barrier Functions, and Colonic Motility

ADAM Proteases and Gastrointestinal Function

Tumour Necrosis Factor Superfamily Members in the Pathogenesis of Inflammatory Bowel Disease

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