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

Marić, Ivana; Kučić, Natalia; Wensveen, Tamara Turk; Smoljan, Ivana; Grahovac, Blaženka; Cvek, Sanja Zoričić; Ćelić, Tanja; Bobinac, Dragica; Vukičević, Slobodan

doi:10.1152/ajpgi.00244.2011

Cited by 23 publications

(25 citation statements)

References 77 publications

(98 reference statements)

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“…However, exogenous BMP-7 application resulted in a significant increase in BMPR2 expression on monocytes and M2 macrophages suggesting an increase in BMP-7 signal transduction activity. Several studies have supplied supporting evidence to the current findings indicating an upregulation of BMPR2 expression at 2 days following BMP-7 administration in various models including TNBS-induced colitis [5], [15]. Of note, following treatment with follistatin, an inhibitor of BMP-7 signal transduction, significant upregulation of BMPR2 on monocytes and M2 macrophages was abolished suggesting a direct relation between BMP-7 signaling and upregulation of BMPR2.…”

Section: Discussionsupporting

confidence: 82%

SMAD-PI3K-Akt-mTOR Pathway Mediates BMP-7 Polarization of Monocytes into M2 Macrophages

2013

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Previously we demonstrated that bone morphogenetic protein-7 (BMP-7) treatment polarizes monocytes into M2 macrophages and increases the expression of anti-inflammatory cytokines. Despite these findings, the mechanisms for the observed BMP-7 induced monocyte polarization into M2 macrophages are completely unknown. In this study, we demonstrate the mechanisms involved in the polarization of monocytes into M2 macrophages. Apoptotic conditioned media (ACM) was generated to mimic the stressed conditions, inducing monocyte polarization. Monocytes were treated with ACM along with BMP-7 and/or its inhibitor, follistatin, for 48 hours. Furthermore, an inhibitor of the PI3K pathway, LY-294002, was also studied. Our data show that BMP-7 induces polarization of monocytes into M2 macrophages while significantly increasing the expression of anti-inflammatory markers, arginase-1 and IL-10, and significantly (p<0.05) decreasing the expression of pro-inflammatory markers iNOS, IL-6, TNF-α and MCP-1; (p<0.05). Moreover, addition of the PI3K inhibitor, LY-294002, significantly (p<0.05) decreases upregulation of IL-10 and arginase-1, suggesting involvement of the PI3K pathway in M2 macrophage polarization. Next, following BMP-7 treatment, a significant (p<0.05) increase in p-SMAD1/5/8 and p-PI3K expression resulting in downstream activation of p-Akt and p-mTOR was observed. Furthermore, expression of p-PTEN, an inhibitor of the PI3K pathway, was significantly (p<0.05) increased in the ACM group. However, BMP-7 treatment inhibited its expression, suggesting involvement of the PI3K-Akt-mTOR pathway. In conclusion, we demonstrate that BMP-7 polarizes monocytes into M2 macrophages and enhances anti-inflammatory cytokine expression which is mediated by the activated SMAD-PI3K-Akt-mTOR pathway.

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Section: Discussionsupporting

confidence: 82%

SMAD-PI3K-Akt-mTOR Pathway Mediates BMP-7 Polarization of Monocytes into M2 Macrophages

2013

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“…Therefore, new types of therapies are needed that can prevent disease or relapse. Several promising options are currently under evaluation in clinical trials and in different animal models of experimental colitis [1,9,12,13]. IBD-like symptoms can be chemically-induced in several animal models, but the mouse model offers several advantages including multiple methods for inducing experimental colitis, a wide array of biochemical and immunological reagents, a well-defined immune system, and the availability of numerous signaling molecule-deficient mice to evaluate treatment specificity [11,14-16].…”

Section: Introductionmentioning

confidence: 99%

Multifunctional role of dextran sulfate sodium for in vivo modeling of intestinal diseases

2012

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BackgroundInflammatory bowel diseases (IBDs) are chronic, relapsing disorders that affect the gastrointestinal tract of millions of people and continue to increase in incidence each year. While several factors have been associated with development of IBDs, the exact etiology is unknown. Research using animal models of IBDs is beginning to provide insights into how the different factors contribute to disease development. Oral administration of dextran sulfate sodium (DSS) to mice induces a reproducible experimental colitis that models several intestinal lesions associated with IBDs. The murine DSS colitis model can also be adapted to quantify intestinal repair following injury. Understanding the mechanistic basis behind intestinal repair is critical to development of new therapeutics for IBDs because of their chronic relapsing nature.ResultsThe murine DSS colitis model was adapted to provide a system enabling the quantification of severe intestinal injury with impaired wound healing or mild intestinal injury with rapid restoration of mucosal integrity, by altering DSS concentrations and including a recovery phase. We showed that through a novel format for presentation of the clinical disease data, the temporal progression of intestinal lesions can be quantified on an individual mouse basis. Additionally, parameters for quantification of DSS-induced alterations in epithelial cell populations are included to provide insights into mechanisms underlying the development of these lesions. For example, the use of the two different model systems showed that toll-like receptor 9, a nucleic acid-sensing pattern recognition receptor, is important for protection only following mild intestinal damage and suggests that this model is superior for identifying proteins necessary for intestinal repair.ConclusionsWe showed that using a murine DSS-induced experimental colitis model system, and presenting data in a longitudinal manner on a per mouse basis, enhanced the usefulness of this model, and provided novel insights into the role of an innate immune receptor in intestinal repair. By elucidating the mechanistic basis of intestinal injury and repair, we can begin to understand the etiology of IBDs, enabling development of novel therapeutics or prophylactics.

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“…Similarly, BMP-7 has been shown to ameliorate the severity of colonic inflammation and to accelerate the healing of colitis in rats exposed to trinitrobenzene sulfonic acid, a well-established inducer of experimental colitis in rodents. 19,20 Finally, transgenic expression of BMP-4 in the skin of mice treated with both the carcinogen N-methyl-N’-nitrosoguanidine and the tumor promoter 12-O-teradecanoylphorbol-13-acetate leads to a marked decrease in the degree of cellular hyperproliferation and inflammation induced by these agents. 24 …”

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confidence: 99%

Anti-Inflammatory Activity of Bone Morphogenetic Protein Signaling Pathways in Stomachs of Mice

et al. 2014

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BACKGROUND & AIMS Bone morphogenetic protein (BMP)4 is a mesenchymal peptide that regulates cells of the gastric epithelium. We investigated whether BMP signaling pathways affect gastric inflammation after bacterial infection of mice. METHODS We studied transgenic mice that express either the BMP inhibitor noggin or the β- galactosidase gene under the control of a BMP-responsive element and BMP4βgal/+ mice. Gastric inflammation was induced by infection of mice with either Helicobacter pylori or Helicobacter felis. Eight to 12 weeks after inoculation, gastric tissue samples were collected and immunohistochemical, quantitative, reverse-transcription polymerase chain reaction and immunoblot analyses were performed. We used enzyme-linked immunosorbent assays to measure cytokine levels in supernatants from cultures of mouse splenocytes and dendritic cells, as well as from human gastric epithelial cells (AGS cell line). We also measured the effects of BMP-2, BMP-4, BMP-7, and the BMP inhibitor LDN-193189 on the expression of interleukin (IL)8 messenger RNA by AGS cells and primary cultures of canine parietal and mucus cells. The effect of BMP-4 on NFkB activation in parietal and AGS cells was examined by immunoblot and luciferase assays. RESULTS Transgenic expression of noggin in mice increased H pylori– or H felis–induced inflammation and epithelial cell proliferation, accelerated the development of dysplasia, and increased expression of the signal transducer and activator of transcription 3 and activation-induced cytidine deaminase. BMP-4 was expressed in mesenchymal cells that expressed α-smooth muscle actin and activated BMP signaling pathways in the gastric epithelium. Neither BMP-4 expression nor BMP signaling were detected in immune cells of C57BL/6, BRE–β-galactosidase, or BMP-4βgal/+ mice. Incubation of dendritic cells or splenocytes with BMP-4 did not affect lipopolysaccharide-stimulated production of cytokines. BMP-4, BMP-2, and BMP-7 inhibited basal and tumor necrosis factor α–stimulated expression of IL8 in canine gastric epithelial cells. LDN-193189 prevented BMP4-mediated inhibition of basal and tumor necrosis factor α–stimulated expression of IL8 in AGS cells. BMP-4 had no effect on TNFα-stimulated phosphorylation and degradation of IκBα, or on TNFα induction of a NFκβ reporter gene. CONCLUSIONS BMP signaling reduces inflammation and inhibits dysplastic changes in the gastric mucosa after infection of mice with H pylori or H felis.

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

Cited by 23 publications

References 77 publications

SMAD-PI3K-Akt-mTOR Pathway Mediates BMP-7 Polarization of Monocytes into M2 Macrophages

SMAD-PI3K-Akt-mTOR Pathway Mediates BMP-7 Polarization of Monocytes into M2 Macrophages

Multifunctional role of dextran sulfate sodium for in vivo modeling of intestinal diseases

Anti-Inflammatory Activity of Bone Morphogenetic Protein Signaling Pathways in Stomachs of Mice

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