Activation of nuclear factor kappa B in inflammatory bowel disease

Schreiber, Stefan; Nikolaus, Susanna; Hampe, Jochen

doi:10.1136/gut.42.4.477

Cited by 678 publications

(517 citation statements)

References 35 publications

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“…Second, while MSP was originally identified as a protein that could elicit macrophage chemotaxis and activation, signaling though the MSP/MST1R has recently been shown to inhibit LPS or cytokine mediated production of inflammatory mediators (such as NO, COX2, PGE2 and IL-12p40) by macrophages, through the inhibition of NfkB signaling (24)(25)(26)(27). Interestingly, increased NfkB signaling activity, as well as increased levels on NO and expression of IL-12p40, have all been observed in the inflamed mucosa of patients with IBD (48)(49)(50). Finally, mice deficient in MST1R show increase susceptibility to septic shock following LPS challenge, highlighting the importance of the MSP/MST1R signaling pathway in controlling inflammation triggered from innate immune responses (41,42).…”

Section: Discussionmentioning

confidence: 93%

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

Goyette

Lefèbvre

et al. 2008

Mucosal Immunology

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Association mapping and candidate gene studies within IBD linkage regions, as well as genomewide association studies in CD have led to the discovery of multiple risk genes, but these only Corresponding author: John D. Rioux, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada, H1T 1C8, rioux@inflammgen.org. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript explain a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and UC using a gene-centric association mapping approach. We identified twelve functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/ intestinal function. We then performed an association study composed of a screening phase, where tagging SNPs were evaluated in 1020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association to IBD for four SNPs within a 1.2 Mb LD region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage stimulating 1 (MST1) gene (p-value 3.62×10−6) that accounts for the association signal, and shows association to both CD and UC. MST1 encodes MSP, a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.

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Section: Discussionmentioning

confidence: 93%

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

Goyette

Lefèbvre

et al. 2008

Mucosal Immunology

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“…NF-B activation is increased in colonic biopsies from IBD patients (Rogler et al, 1998;Schreiber et al, 1998), macrophages and epithelial cells isolated from inflamed IBD tissue have high levels of p65 (Rogler et al, 1998), and the level of activated NF-B correlates with the severity of disease (Rogler et al, 1998). In epithelial cells, NF-B not only contributes to the pathogenesis of IBD by altering intestinal barrier function but also activates proinflammatory signaling, potentiating the production of other proinflammatory cytokines by epithelial cells and promoting the inflammatory process.…”

Section: Discussionmentioning

confidence: 99%

Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

Theiss

Jenkins

Okoro

et al. 2009

MBoC

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“…NF-B regulates the transcription of a number of proinflammatory molecules, including IL-1␤, tumor necrosis factor-␣, IL-6, IL-8, IL-12, inducible nitric-oxide synthase, ICAM-1, VCAM-1, and major histocompatibility complex class II molecules, involved in acute responses to injury and in chronic intestinal inflammation (23,24). NF-B activation has been documented in the intestine of patients with various forms of inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, and self-limited colitis (25)(26)(27). Immunohistochemistry performed on tissue sections isolated from patients with inflammatory bowel disease demonstrates the presence of activated NF-B in IECs located at the crypts but not at the surface region (26).…”

Section: Discussionmentioning

confidence: 99%

Polyamine Depletion Induces Rapid NF-κB Activation in IEC-6 Cells

Pfeffer¹,

Yang²,

Murti³

et al. 2001

Journal of Biological Chemistry

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The proliferation of the rat intestinal mucosal IEC-6 cell line requires polyamines, whose synthesis is catalyzed by the enzyme ornithine decarboxylase (ODC). ODC inhibition leads to polyamine depletion, as well as inhibition of both cell proliferation and apoptosis by regulating gene expression. The NF-B transcription factor regulates genes involved in apoptotic, immune, and inflammatory responses. In the present study we tested the hypothesis that NF-B is activated following ODC inhibition. We found that the inhibition of ODC by ␣-difluoromethylornithine (DFMO) resulted in a ϳ50% decrease in intracellular putrescine levels within 1 h. NF-B is activated by DFMO through the degradation of the inhibitory protein IB␣ that sequesters NF-B in the cytoplasm. The DFMO-induced NF-B complexes contain the p65 and p50 members of the Rel protein family. DFMO-induced NF-B activation was accompanied by the translocation of p65 from the cytoplasm into the nucleus. DFMO selectively inhibited a gene reporter construct dependent on the B site present in the HLA-B7 gene. In contrast, DFMO had no effect on a gene reporter construct dependent on the B site present in the interleukin-8 gene. Thus, we report that ODC inhibition activates the NF-B transcription factor, which may mediate the altered physiological state of intestinal cells that occurs following polyamine depletion.

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Activation of nuclear factor kappa B in inflammatory bowel disease

Abstract: (Gut 1998;42:477-484)

Cited by 678 publications

References 35 publications

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

Polyamine Depletion Induces Rapid NF-κB Activation in IEC-6 Cells

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