Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway

Ulloa, Luis; Doody, Jacqueline; Massagué, Joan

doi:10.1038/17826

Cited by 772 publications

(574 citation statements)

References 30 publications

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“…Regarding the IFN-g multiple effects including immunomodulation, inhibition of tumor cell proliferation, tumor cells apoptosis, and TGF-b1 downregulation, 8 we investigated the effects of IFN-g gene expression in this model.…”

Section: Discussionmentioning

confidence: 99%

“…IFN-g was shown by others to inhibit TGF-b signaling by inducing the antagonist Smad7 and may thus inhibit TGF-b-induced angiogenesis. 8 This indirect effect on stroma cells may contribute to tumor regression. In the present study, we found that Smad2 expression was downregulated in Ad-IFNg-infected cells (Fig 3a), but we were unable to detect Smad7 upregulation in AK7 infected cells.…”

Section: Discussionmentioning

confidence: 99%

“…IFN-g has opposite effects to TGF-b as recently demonstrated by the induction of Smad7 expression, which prevents the interaction of Smad3 with the TGF-b receptor. 8 IFN-g therefore inhibits the TGF-b activation of Smad3 and may prevent the immunosuppressive effect of TGF-b. Furthermore, IFN-g directly stimulates host immune response by inducing the expression of MHC class I and class II molecules.…”

Section: Alignant Mesothelioma (Mm) Is An Aggressivementioning

confidence: 99%

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Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma

et al. 2003

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Malignant mesothelioma (MM) is a lethal tumor linked with a prior exposure to asbestos in which limited progress has been made so far using conventional therapies. MM is an example of a ''nonimmunogenic'' tumor characterized by a fibrous stroma and an absence of infiltrating T lymphocytes. High levels of transforming growth factor-beta (TGF-b) produced by mesothelioma cells have been related to the immune tolerance towards the tumor. In order to evaluate the effect of local delivery of cytokines such as interferon gamma (IFN-g) by gene transfer, we characterized and used a murine model, AK7, which appeared very similar to human mesothelioma. AK7 cells expressed low levels of major histocompatibility class I and class II antigens and secreted high levels of latent TGF-b. The TGF-b pathway in AK7 cells is operative but inefficient because endogenous TGF-b is predominantly inactive. Treatment of pre-established AK7 tumors by direct intratumoral injection of an adenovirus vector expressing murine IFN-g, Ad.mIFN-g, led to significant tumor regression. Peripheral tumor infiltration by CD4+ and CD8+ T lymphocytes in the treated tumors appeared to be because of the induction of an immune response. Tumor relapse was observed, which could be due to local TGF-b secretion by remaining tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Alignant Mesothelioma (Mm) Is An Aggressivementioning

confidence: 99%

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Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma

et al. 2003

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“…There may be crosstalk between these signaling pathways and the signal transduction pathways activated by BMPs. 34,35 Both Type I and Type II BMP receptors are serine/ threonine kinases. The Type II receptors are constitutive active serine/threonine kinase receptors.…”

Section: Bone Volumes Induced By Adhbmp4 and Adhbmp9 In Different Groupsmentioning

confidence: 99%

Local immunomodulation with CD4 and CD8 antibodies, but not cyclosporine A, improves osteogenesis induced by ADhBMP9 gene therapy

Hankins

et al. 2005

Gene Ther

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This study was designed to see if immunosuppression achieved using local application of cyclosporine A (Cs. A) or CD4 and CD8 antibodies would improve bone formation following intramuscular injections of human BMP-4 and BMP-9 adenoviral vectors (ADhBMP4 and ADhBMP9) in Sprague-Dawley rats. Cs. A was injected into the thigh muscle. After 2 days, ADhBMP4, ADhBMP9, and the antibodies were separately injected into the left and right rear legs. At this time, the number of CD4+/CD3+ cells was significantly lower and the number of CD8+/CD3+ cells higher in the Cs. A group than in the control group (Po0.01). The total number of white blood cells 3 days following injection of CD4 and CD8 antibodies was significantly lower than that before the injection (Po0.01). At 4 weeks after the viral and antibody injections, mean bone volumes at the ADhBMP9 treatment sites were 0.2970.01 cm 3 in the viral control group, 0.1770.03 cm 3 in the Cs. A-ADhBMPs group, and 0.5970.07 cm 3 in the antibodies-ADhBMPs group. ADhBMP4 did not induce new bone formation in any group. This study demonstrates that local immunomodulation may improve the osteogenic potential of bone morphogenetic protein gene therapy in the clinical setting.

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“…The expression of Smad7 is increased significantly by interferon-␥ (IFN-␥). 33 In addition, IFN-␥ decreases the production of latent TGF-␤1 complex by macrophages in a dose dependent fashion. 34 IFN-␥ receptors are present in almost all cell types with the exception of mature erythrocytes.…”

Section: Regulation Of Tgf-␤1mentioning

confidence: 99%

Current concepts in radiation enteritis and implications for future clinical trials

Nguyen

Antoine

Dutta

et al. 2002

Cancer

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BACKGROUNDRadiation enteritis is one of the most feared complications of abdominal and pelvic radiation. Once its occurs, the process is relentless and may result in the patient's death. Available treatment is only supportive. Recent progress in molecular biology has shed some light on the pathogenesis of radiation enteritis and other diseases that are characterized by excessive fibrosis. New treatment modalities may be devised to improve the outcome of patients who are affected with this complication.METHODSA literature search was used to identify the common denominator between many radiation‐induced fibrotic conditions and other sclerotic diseases. Factors that affect the disease process and possible therapeutic interventions were evaluated.RESULTSThe hyperstimulation of transforming growth factor β1 (TGF‐β1) leads to increased fibrosis and, ultimately, organ failure. Interferon gamma (IFN‐γ) inhibits the effects of TGF‐β1 in the nucleus. The fibrotic process may be reverted by IFN‐γ in various pathologic conditions.CONCLUSIONSRadiation enteritis and other radiation‐induced, long‐term complications are characterized by excessive stimulation of TGF‐β1. Preliminary studies suggest that IFN‐γ may be effective in the treatment of patients with radiation‐induced cutaneous fibrosis. IFN‐γ should be considered in Phase I–II studies to assess its toxicity and efficacy in the treatment of patients with radiation enteritis. Cancer 2002;95:1151–63. © 2002 American Cancer Society.DOI 10.1002/cncr.10766

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Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway

Cited by 772 publications

References 30 publications

Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma

Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma

Local immunomodulation with CD4 and CD8 antibodies, but not cyclosporine A, improves osteogenesis induced by ADhBMP9 gene therapy

Current concepts in radiation enteritis and implications for future clinical trials

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