Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation

Goode, Triona; O’Connell, Joseph; Anton, Peter A.; Wong, Helen; Reeve, Joseph R.; O'Sullivan, G.C.; Collins, John; Shanahan, Fergus

doi:10.1136/gut.47.3.387

Cited by 130 publications

(133 citation statements)

References 45 publications

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“…Also revealed was the importance of IL-12 and IL-10 for the control of mucosal T cell NK-1R expression. This may be physiologically important, since NK-1R is heavily expressed on mucosal T cells in human IBD (10). The piroxicam-IL-10 model of IBD will allow further exploration into the roles of tachykinins and their receptors in the control of intestinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Weinstock

Blum

Metwali

et al. 2003

The Journal of Immunology

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Substance P (SP) is a proinflammatory molecule that interacts with a neurokinin 1 receptor (NK-1R), which is on T cells and helps control IFN-γ production. IL-10−/− mice given a nonsteroidal anti-inflammatory drug (NSAID) develop Th1 colitis. We studied the importance of SP and NK-1R in this colitis model. LP T cells were isolated to study their NK-1R expression. LP T cells from IL-10−/− mice expressed NK-1R and produced IFN-γ only after NSAID treatment and induction of colitis. LP T cells from NSAID-treated wild-type controls or from age-matched untreated IL-10−/− animals did not express NK-1R or produce IFN-γ. Experiments showed that IL-12 induced NK-1R transcription in CD4+ T cells cultured in vitro. However, T cells cultured with IL-12 and IL-10 did not express NK-1R. IL-10 also down-modulated ongoing NK-1R expression. Mice given NK-1R antagonist after NSAID induction of severe colitis showed nearly complete reversal of inflammation, and LP T cells ceased IFN-γ secretion. Thus, intestinal inflammation in IL-10−/− mice is associated with the appearance of NK-1R in mucosal T cells, and an interplay between IL-12 and IL-10 regulates T cell NK-1R transcription. NK-1R antagonist reverses ongoing intestinal inflammation attesting to the importance of SP and its receptor in mucosal inflammation.

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Section: Discussionmentioning

confidence: 99%

“…In human IBD there is increased NK-1R mRNA expression (9) in the tissue. Goode et al (10) showed, using quantitative PCR, a 7-fold increase in NK-1R transcripts in CD colon and a somewhat more modest increase in ulcerative colitis. Compared with normal control colon, however, immunohistochemistry revealed no ectopic sites of NK-1R expression.…”

mentioning

confidence: 99%

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Weinstock

Blum

Metwali

et al. 2003

The Journal of Immunology

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“…For this reason, NK1 receptor antago-nists are used as antidepressants (Fuchs et al 2005). Several reports have demonstrated the presence of NK1R in different neuronal and non-neuronal cells in the gastrointestinal tract (Sternini et al 1995;Goode et al 2000). In pathological states, such as inflammation in Crohn's disease, NK1R expression is up-regulated (Renzi et al 2000).…”

Section: Oryctolagus Cuniculus Nk2r Sus Scrofa Nk2rmentioning

confidence: 99%

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Jakimiuk¹,

Podlasz²,

Chmielewska-Krzesińska³

et al. 2017

Vet. Med.

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Substance P is involved in many physiological and pathophysiological processes. This functional diversity is mediated by three neurokinin receptor subtypes (NK1R, NK2R and NK3R) encoded by the TACR1, TACR2 and TACR3 genes, respectively. Despite the increasing interest in using pigs (Sus scrofa) to study human disease mechanisms, the sequences of these receptors are still unconfirmed or in the case of the NK1 receptor, not yet even unpredicted. We employed in silico analysis to define the localisation of the porcine tachykinin receptor genes, and to predict the structures and amino acid sequences of the respective proteins. A reverse transcription polymerase chain reaction (RT-PCR) assay was performed to analyse the expression of tachykinin receptor genes in different porcine tissues. The data show that the TACR1 gene is located on chromosome 3, TACR2 on chromosome 14 and TACR3 on chromosome 8. All three genes encode proteins with structures that incorporate features of G-protein-coupled receptors with sizes of 407, 381 and 464 amino acids, respectively. The receptors display a high degree of similarity to other mammalian neurokinin receptors. The NK1R subtype is expressed in both the central nervous system and peripheral tissues, while NK2R expression seems to be localised mostly to peripheral tissues. The expression of NK3R is found mainly in the central nervous system. This report provides for the first time the results of a comprehensive analysis of the structure and distribution of porcine NK1R, as well as other porcine neurokinin receptors and their genes. We hope that our data may offer an invaluable foundation for the future studies on the function of diverse tachykinin peptides in the central nervous system and peripheral tissues.

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“…The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation (9,10) and in patients with UC as well as Crohn disease (11)(12)(13)(14). However, not all of these studies are in agreement regarding epithelial NK-1R expression in UC: some studies have shown an increase (12,13), whereas others have not (11,14). The NK-1R has been identified in many cancers, including skin, gastrointestinal, laryngeal, pancreatic, ovarian, brain, thyroid, and breast cancers (15)(16)(17)(18)(19).…”

mentioning

confidence: 99%

“…SP's primary receptor, the neurokinin-1 receptor (NK-1R), can mediate a variety of physiologic and pathophysiologic responses, including cell proliferation, migration, and inflammation (8). The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation (9,10) and in patients with UC as well as Crohn disease (11)(12)(13)(14). However, not all of these studies are in agreement regarding epithelial NK-1R expression in UC: some studies have shown an increase (12,13), whereas others have not (11,14).…”

mentioning

confidence: 99%

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitisassociated cancer.colon cancer | receptor splice variants | substance P | IBD C hronic inflammation is associated with a higher rate of cancer development in various organs (1). More specifically, patients with ulcerative colitis (UC) are at high risk for developing colorectal cancer (2); both extent and duration of intestinal inflammation further increase risk (3, 4). These associations suggest that chronic intestinal inflammation is a causative factor in carcinogenesis in patients with UC, and that there is a causal link between chronic inflammation and increased risk of cancer. These observations raise the question of the signaling pathways by which long-standing inflammation might underlie the development of cancer.Substance P (SP) is a proinflammatory neuropeptide described by von Euler and Gaddum (5) and later isolated and characterized by Chang and Leeman (6). SP is synthesized by a variety of cells, most notably neurons and inflammatory cells such as macrophages (7). SP's primary receptor, the neurokinin-1 receptor (NK-1R), can mediate a variety of physiologic and pathophysiologic responses, including cell proliferation, migration, and inflammation (8). The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation (9, 10) and in patients with UC as well as Crohn disease (11)(12)(13)(14). However, not all of these studies are in agreement regarding epithelial NK-1R e...

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Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation

Cited by 130 publications

References 45 publications

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

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