Transforming growth factor-β inhibits surfactant protein A expression in vitro

We reported an association between the ability of recombinant human keratinocyte growth factor (rHuKGF) to upregulate the expression of surfactant protein A (SP-A) and to downregulate pulmonary inflammation that occurs after allogeneic bone marrow transplantation (BMT). To establish a causal relationship, rHuKGF (5 mg/kg) was administered subcutaneously for three consecutive days before irradiation to SP-A-sufficient and -deficient [SP-A(+/+) and SP-A(-/-), respectively] mice given inflammation-inducing allogeneic spleen T cells at the time of BMT. In contrast with SP-A(+/+) mice, rHuKGF failed to suppress the high levels of TNF-α, IFN-γ, and nitric oxide contained in bronchoalveolar lavage fluids collected on day 7 after BMT from SP-A(-/-) mice. Early post-BMT weight loss was attenuated by rHuKGF in both SP-A(+/+) and SP-A(-/-) recipients. In the absence of supportive respiratory care, however, SP-A deficiency eventually abolished the ability of rHuKGF to prevent weight loss and to improve survival monitored for 1 mo after allogeneic BMT. In further experiments, the addition of cyclophosphamide (which is known to cause severe injury to the alveolar epithelium in donor T cell-recipient mice) to the conditioning regimen prevented rHuKGF-induced upregulation of SP-A and suppression of lung inflammation in both SP-A(+/+) and SP-A(-/-) mice. We conclude that endogenous baseline SP-A levels and optimal upregulation of SP-A are required for the anti-inflammatory protective effects of KGF after allogeneic transplantation.

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Targeting Transforming Growth Factor-β in Metastasis: In Vitro and In Vivo Mechanisms

Transforming Growth Factor-β in Cancer Therapy, Volume II ◽

10.1007/978-1-59745-293-9_37 ◽

2008 ◽

pp. 609-634 ◽

Cited By ~ 1

Author(s):

Michael Reiss

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β

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Effects of Gamma Interferon, Interleukin-10, and Transforming Growth Factor β on the Survival of Mycobacterium avium subsp. paratuberculosis in Monocyte-Derived Macrophages from Naturally Infected Cattle

Infection and Immunity ◽

10.1128/iai.72.4.1974-1982.2004 ◽

2004 ◽

Vol 72 (4) ◽

pp. 1974-1982 ◽

Cited By ~ 52

Author(s):

M. S. Khalifeh ◽

J. R. Stabel

Keyword(s):

Growth Factor ◽

Cell Cultures ◽

Mycobacterium Avium ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Interleukin 10 ◽

Gamma Interferon ◽

Ifn Γ ◽

Culture Supernatants

ABSTRACT Gamma interferon (IFN-γ) plays a significant role in the control of mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis. However, the contribution of other immunoregulatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor β (TGF-β), in Johne's disease has not been investigated as yet. In this study, we examined the effects of in vivo and in vitro infection with M. avium subsp. paratuberculosis on the production of IFN-γ, IL-10, and TGF-β by peripheral blood mononuclear cells (PBMC). We also examined the effects of exogenous IFN-γ, IL-10, and TGF-β on M. avium subsp. paratuberculosis survival in the cell cultures. PBMC obtained from naturally infected cows, regardless of their disease status, specifically upregulated IL-10 and TGF-β in culture supernatants in response to stimulation with live M. avium subsp. paratuberculosis. Nonstimulated PBMC recovered from subclinically infected animals secreted the lowest levels of TGF-β, but after stimulation with live M. avium subsp. paratuberculosis, TGF-β levels in the culture supernatants increased to levels similar to that produced by PBMC from healthy animals. The numbers of viable M. avium subsp. paratuberculosis recovered from cultures from naturally infected animals were higher than those from healthy cows after in vitro infection with M. avium subsp. paratuberculosis. The addition of exogenous IL-10 and TGF-β to PBMC isolated from healthy cows inhibited the bactericidal activity of these cells as evidenced by the increased number of viable M. avium subsp. paratuberculosis recovered from these cultures compared to cell cultures containing medium alone. These data suggest important immune regulatory roles for IL-10 and TGF-β during infection with M. avium subsp. paratuberculosis that may be directly related to their effects on macrophage activation and killing of M. avium subsp. paratuberculosis.

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The Activity of Differentiation Factors Induces Apoptosis in Polyomavirus Large T-Expressing Myoblasts

Molecular Biology of the Cell ◽

10.1091/mbc.9.6.1449 ◽

1998 ◽

Vol 9 (6) ◽

pp. 1449-1463 ◽

Cited By ~ 22

Author(s):

Gian Maria Fimia ◽

Vanesa Gottifredi ◽

Barbara Bellei ◽

Maria Rosaria Ricciardi ◽

Agostino Tafuri ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Growth Factor ◽

Cell Cycle Progression ◽

Transforming Growth Factor ◽

Myogenic Differentiation ◽

Transforming Growth Factor Β ◽

Large Tumor ◽

Cycle Progression

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor β or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G00arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis.

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Cellular crosstalk mediated by platelet-derived growth factor BB and transforming growth factor β during hepatic injury activates hepatic stellate cells

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0768 ◽

2018 ◽

Vol 96 (8) ◽

pp. 728-741 ◽

Cited By ~ 7

Author(s):

Sowmya Mekala ◽

SubbaRao V. Tulimilli ◽

Ramasatyaveni Geesala ◽

Kanakaraju Manupati ◽

Neha R. Dhoke ◽

...

Keyword(s):

Growth Factor ◽

Hepatic Stellate Cells ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Stellate Cells ◽

Transforming Growth Factor Β ◽

Platelet Derived Growth Factor ◽

Hepatic Tissue

Apoptotic hepatocytes release factors that activate hepatic stellate cells (HSCs), thereby inducing hepatic fibrosis. In the present study, in vivo and in vitro injury models were established using acetaminophen, ethanol, carbon tetrachloride, or thioacetamide. Histology of hepatotoxicant-induced diseased hepatic tissue correlated with differential expression of fibrosis-related genes. A marked increase in co-staining of transforming growth factor β receptor type II (TGFRIIβ) – desmin or α-smooth muscle actin – platelet-derived growth factor receptor β (PDGFRβ), markers of activated HSCs, in liver sections of these hepatotoxicant-treated mice also depicted an increase in Annexin V – cytokeratin expressing hepatocytes. To understand the molecular mechanisms of disease pathology, in vitro experiments were designed using the conditioned medium (CM) of hepatotoxicant-treated HepG2 cells supplemented to HSCs. A significant increase in HSC proliferation, migration, and expression of fibrosis-related genes and protein was observed, thereby suggesting the characteristics of an activated phenotype. Treating HepG2 cells with hepatotoxicants resulted in a significant increase in mRNA expression of platelet-derived growth factor BB (PDGF-BB) and transforming growth factor β (TGFβ). CM supplemented to HSCs resulted in increased phosphorylation of PDGFRβ and TGFRIIβ along with its downstream effectors, extracellular signal-related kinase 1/2 and focal adhesion kinase. Neutralizing antibodies against PDGF-BB and TGFβ effectively perturbed the hepatotoxicant-treated HepG2 cell CM-induced activation of HSCs. This study suggests PDGF-BB and TGFβ as potential molecular targets for developing anti-fibrotic therapeutics.

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