Smad7 in TGF-β-mediated negative regulation of gut inflammation

Monteleone, Giovanni; Pallone, Francesco; MacDonald, Thomas T.

doi:10.1016/j.it.2004.07.008

Cited by 135 publications

(128 citation statements)

References 45 publications

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“…This defect was associated with no significant change in the intracellular levels of phosphorylated Smad3 and Smad7, clearly indicating that initial steps of TGF-b signaling are preserved in patients with active CD [33] . This is in contrast to the Smad7-dependent inhibition of TGF-b1/Smad3 signaling described in patients with inflammatory bowel diseases [34,35] . IELs, lamina propria lymphocytes, and epithelial cells of active CD contain high levels of phospho-c-jun, and inhibition of this protein in organ cultures of CD biopsies enhances tristetraprolin [33] .…”

Section: Il-15 and Counter-regulatory Mechanisms In CDcontrasting

confidence: 84%

Involvement of interleukin-15 and interleukin-21, two γ-chain-related cytokines, in celiac disease

Nitto¹,

Monteleone²,

Franzè³

et al. 2009

WJG

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Celiac disease (CD), an enteropathy caused by dietary gluten in genetically susceptible individuals, is histologically characterized by villous atrophy, crypt cell hyperplasia, and increased number of intra-epithelial lymphocytes. The nature of CD pathogenesis remains unclear, but recent evidence indicates that both innate and adaptive immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD. Extensive studies of molecules produced by immune cells in the gut of CD patients have led to identification of two cytokines, namely interleukin (IL)-15 and IL-21, which are thought to play a major role in orchestrating the mucosal inflammatory response in CD. Here we review the current knowledge of the expression and function of IL-15 and IL-21 in CD.

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Section: Il-15 and Counter-regulatory Mechanisms In CDcontrasting

confidence: 84%

Involvement of interleukin-15 and interleukin-21, two γ-chain-related cytokines, in celiac disease

Nitto¹,

Monteleone²,

Franzè³

et al. 2009

WJG

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“…The findings of pSmad 1/5/8 in the enteric plexus pointed to another possible effect of preserved BMP pathway to arrest the smooth muscle dysfunction, which was observed in TNBS colitis as the outcome of both oxidative stress and proinflammatory cytokines, specifically IGF-1 and TGF-␤ (58). In vivo regulation of Smad molecules is dependent not only on the ligand application but also on the BMP pathway modulation by RAS/ERK, TLR-IL-1R, or Wnt pathways (8,15,30,50). It was also shown that Dragon, repulsive guidance molecule (RGM) family member, enhanced the BMP signaling activity and decreased the IL-6 expression in a BMP-ligand-dependent manner via a non-Smad pathway, like p38MAPK and Erk1/2 (70).…”

Section: Discussionmentioning

confidence: 99%

BMP signaling in rats with TNBS-induced colitis following BMP7 therapy

Marić¹,

Kučić

Wensveen

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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yond stimulating bone formation, bone morphogenetic proteins (BMPs) are important in development, inflammation, and malignancy of the gut. We have previously shown that BMP7 has a regenerative, anti-inflammatory, and antiproliferative effect on experimental inflammatory bowel disease (IBD) in rats. To further investigate the BMP signaling pathway we monitored the effect of BMP7 therapy on the BMP signaling components in the rat colon during different stages of experimentally induced colitis by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The results showed a significantly decreased BMP7 expression in the acute phase, followed by a significantly increased BMP2 and decreased BMP6 expression during the chronic phase of colitis. BMP7 therapy influenced the expression of several BMPs with the most prominent effect on downregulation of BMP2 and upregulation of BMP4 in the chronic phase of colitis. Importantly, connective tissue growth factor and noggin expression were elevated in the acute stage and significantly decreased upon BMP7 therapy. BMP receptor I expression was unchanged, whereas BMP receptor II was decreased at day 2 and increased at days 14 and 30 of TNBS inflammation. However, an opposite pattern of expression following BMP7 therapy has been observed. BMP7 increased the expression of BR-Smad including Smad3 and Smad4. Inhibitory Smads were increased in colitis and significantly decreased following BMP7 therapy at later stages of the disease. We suggest that BMP signaling was altered during TNBS-induced colitis and was recovered with BMP7 administration, suggesting that IBD is a reversible process.

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“…TGF-␤1 has previously been investigated in several intestinal inflammatory conditions (14,15) and is known for its potent effects in mitigating mucosal inflammation, although less is known about its expression during the resolution of sepsis. Animal studies have shown that septic mice with TGF-␤1 gene deletions develop spontaneous organ failure associated with infiltration of MNCs, which indicates that this gene may play a role in controlling inflammatory responses (16).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Cow's Milk Protein-Specific Inflammatory and Regulatory Cytokine Responses in Preterm Infants With Necrotizing Enterocolitis and Sepsis

et al. 2011

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Enteral feeding with cow's milk formula is associated with neonatal necrotizing enterocolitis (NEC) and sepsis. Dietary antigen sensitization may play a role in promoting and/or sustaining inflammation in both conditions. Aiming at investigating cow's milk protein (CMP)-specific cytokine responses in preterm infants with NEC and sepsis, 14 babies with NEC, 14 matched healthy controls, and 10 septic controls were recruited. Unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) secreting IFN-␥, IL-4, IL-10, and TGF-␤1 were counted by the single-cell enzyme-linked immunospot (ELISPOT) assay. During the acute phase of NEC, patients showed a general pattern of a high level of cytokine secretion both when unstimulated and stimulated by mitogen [phytohaemagglutinin (PHA)] and CMPs: beta-lactoglobulin (␤-lg) and casein. These responses were more marked to ␤-lg for IFN-␥, IL-4, and IL-10 than TGF-␤1. Cytokine responses in sepsis were lower than in NEC (lowest in healthy controls, with a minimal TGF-␤1 response). At term, lower frequencies of cytokine-secreting cells were elicited than during the acute phase, except for TGF-␤1 secreting cells, which increased at term (in response to PHA and CMPs) particularly following not only NEC but also sepsis.

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Smad7 in TGF-β-mediated negative regulation of gut inflammation

Cited by 135 publications

References 45 publications

Involvement of interleukin-15 and interleukin-21, two γ-chain-related cytokines, in celiac disease

Involvement of interleukin-15 and interleukin-21, two γ-chain-related cytokines, in celiac disease

BMP signaling in rats with TNBS-induced colitis following BMP7 therapy

In Vitro Cow's Milk Protein-Specific Inflammatory and Regulatory Cytokine Responses in Preterm Infants With Necrotizing Enterocolitis and Sepsis

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