Resistin-like molecule β regulates intestinal mucous secretion and curtails TNBS-induced colitis in mice

Krimi, Rim Belharbi; Kotelevets, Larissa; Dubuquoy, Laurent; Plaisancié, Pascale; Walker, Francine; Lehy, Thérèse; Desreumaux, Pierre; Seuningen, Isabelle Van; Chastre, Eric; Forgue‐Lafitte, Marie‐Elisabeth; Marie, Jean‐Claude

doi:10.1002/ibd.20420

Cited by 84 publications

(76 citation statements)

References 54 publications

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“…3C). This notion is supported by the recently reported observation that fetal calf serum induces the expression of RELM␤ in vitro (25). Although inhibition of the IGF-I receptor (IGFR) significantly reduced RELM␤ expression, a slightly more significant reduction was observed when both EGFR and IGFR were inhibited simultaneously.…”

Section: Pharmacological Inhibition Of Akt and Growth Factor Signalinmentioning

confidence: 53%

Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways

Wang¹,

Keilbaugh²,

Cash-Mason³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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In the intestinal epithelium, activation of phosphatidylinositol 3-kinase (PI3-kinase)/AKT pathways, via growth factor-mediated signaling, has been shown to regulate cell proliferation and inhibit apoptosis. An immune-activated receptor critical for Th2 immune responses, IL-4Rα can also activate PI3-kinase via insulin receptor substrate (IRS)-dependent signaling. Here, using the intestinal goblet cell-specific gene RELMβ, we investigated the effect of PI3-kinase activation via Th2 immune responses on the goblet cell phenotype. IL-13 stimulation activated PI3-kinase and AKT signal transduction in LS174T cells. Not only did pharmacological inhibition of PI3-kinase and AKT1/2 inhibit RELMβ induction by IL-13, but AKT inhibition also significantly reduced constitutive basal expression of RELMβ, a response reproduced by the simultaneous pharmacological inhibition of both epidermal growth factor receptor and IGF-I receptor signaling. In vivo, the disruption of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), an inhibitor of PI3-kinase activation, led to the activation of RELMβ expression in the small intestine. Furthermore, induction of an intestinal Th2 immune response by infection with a small intestinal nematode parasite, Heligmosomoides polygyrus, led to enhanced epithelial cell proliferation, activation of AKT as demonstrated by the loss of Foxo1 nuclear localization, and robust induction of RELMβ expression in wild-type, but not IL-4Rα knockout, mice. These results demonstrate that Th2 immune responses can regulate goblet cell responses by activation of PI3-kinase and AKT pathways via IL-4Rα.

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Section: Pharmacological Inhibition Of Akt and Growth Factor Signalinmentioning

confidence: 53%

Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways

Wang¹,

Keilbaugh²,

Cash-Mason³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…It has been previously shown that recombinant RELM-␤ can evoke a significant increase in MUC2 gene expression in HT29-C1.16E cells, as well as an increase in Muc2 secretion by murine intestinal goblet cells (28). In the same study, pretreatment of mice with RELM-␤ was shown to significantly attenuate trinitrobenzene sulfonic acid (TNBS)-induced colitis (28). Another goblet cell marker, TFF-3, has been shown to protect epithelial cells by contributing in mucosal defense (3).…”

mentioning

confidence: 97%

Fusobacterium nucleatum Infection of Colonic Cells Stimulates MUC2 Mucin and Tumor Necrosis Factor Alpha

et al. 2011

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The etiology of inflammatory bowel disease is not completely known, but it is influenced by the presence of normal gut microflora as well as yet-unrecognized pathogens. The anaerobic, Gram-negative bacterial species Fusobacterium nucleatum is a common resident of the human mouth and gut and varies in its pathogenic potential. In this study, we demonstrate that highly invasive F. nucleatum isolates derived from the inflamed guts of Crohn's disease patients evoked significantly greater MUC2 and tumor necrosis factor alpha (TNF-␣) gene expression than minimally invasive strains isolated from the noninflamed gut in human colonic epithelial cells and in a rat ligated colonic loop model of infection. Only live F. nucleatum induced mucin secretion and TNF-␣ expression in direct contact with and/or during invasion of colonic cells. In rat colons, mucin secretion was augmented in response to a highly invasive F. nucleatum isolate but was unaffected by treatment with a minimally invasive strain. Taken together, these studies reveal that F. nucleatum may represent a challenging pathogen in the etiology of gut inflammatory diseases and highlight the importance of different pathotypes of candidate bacterial species in disease pathogenesis.

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“…The importance of the Muc2 mucin in organizing the colon mucus protection is further strengthen by the report that two mouse strains with diarrhea and colon inflammation were shown to have two separate spontaneous mutations in the Muc2 mucin (Heazlewood et al 2008). Importantly, the production of mucin is regulated by protein kinases, for example, resistin and resistin-like molecule (RELM) beta upregulated mucin expression which dependent on the kinase activities of protein kinase C (PKC), tyrosine kinases, and extracellular-regulated protein kinase (Krimi et al, 2008); Cathelicidin stimulates colonic mucus synthesis by up-regulating MUC1 and MUC2 expression through a mitogen-activated protein kinase pathway (Tai et al, 2008).…”

Section: Mucus Layermentioning

confidence: 86%

Pathogenesis of Inflammatory Bowel Diseases

Yan¹

2012

Inflammatory Bowel Disease - Advances in Pathogenesis and Management

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Resistin-like molecule β regulates intestinal mucous secretion and curtails TNBS-induced colitis in mice

Abstract: A direct participation in maintaining the mucosal defense barrier can be ascribed to RELMbeta in line with a regulatory role in intestinal inflammation.

Cited by 84 publications

References 54 publications

Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways

Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways

Fusobacterium nucleatum Infection of Colonic Cells Stimulates MUC2 Mucin and Tumor Necrosis Factor Alpha

Pathogenesis of Inflammatory Bowel Diseases

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