Activation of the TGF- β /Activin-Smad2 Pathway during Allergic Airway Inflammation

Rosendahl, Alexander; Checchin, Daniella; Fehniger, Thomas E.; Dijke, Peter ten; Heldin, Carl‐Henrik; Sideras, Paschalis

doi:10.1165/ajrcmb.25.1.4396

Cited by 118 publications

(125 citation statements)

References 35 publications

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“…These finding are consistent with the observations by Rosendahl et al (46). Our data from a murine model of asthma using MC-deficient mice also suggest that MC are an important contributor of elevated activin A level in the asthmatic airway.…”

Section: Discussionsupporting

confidence: 93%

Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells

Cho¹,

Yao²,

Wang³

et al. 2003

The Journal of Immunology

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Activin A, a homodimeric protein (βAβA) and a member of the TGF-β superfamily, is involved in the inflammatory repair process. Using cDNA microarray analysis, we discovered strong induction of the activin βA gene in human mast cells (MC) on stimulation with PMA and calcium ionophore (A23187). Activin βA mRNA was also highly induced in primary cultured murine bone marrow MC (BMMC) after stimulation by IgE receptor cross-linking. Secretion of activin A was evident in human mast cell-1 line cells 3 h after stimulation and progressively increased over time. Activin A was present in the cytoplasm of activated but not unstimulated murine bone marrow MC as demonstrated by immunofluorescence studies, suggesting that secretion of activin A by MC was due to de novo synthesis rather than secretion of preformed protein. Activin A also colocalized with human lung MC from patients with asthma by double-immunofluorescence staining. Furthermore, secretion of activin A was significantly increased in the airway of wild-type mice after OVA sensitization followed by intranasal challenge. Secretion of activin A, however, was greatly reduced in MC-deficient WBB6F1-W/Wv mice as compared with wild-type mice, indicating that MC are an important contributor of activin A in the airways of a murine asthma model. Additionally, activin A promoted the proliferation of human airway smooth muscle cells. Taken together, these data suggest that MC-derived activin A may play an important role in the process of airway remodeling by promoting the proliferation of airway smooth muscle.

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Section: Discussionsupporting

confidence: 93%

Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells

Cho¹,

Yao²,

Wang³

et al. 2003

The Journal of Immunology

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“…Smad2 is of interest since phosphorylated Smad2 (pSmad2) expression has been found to be increased in the epithelium of individuals with asthma as determined by immunostaining in clinical biopsies (16) and in the lungs of ovalbumin (OVA)-challenged mice (17). Ectopic Smad2 expression has also been shown to enhance TGF-b-induced epithelial-mesenchymal transition in vitro (18).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Gregory

Mathie

Walker

et al. 2010

Am J Respir Crit Care Med

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Rationale: Airway hyperreactivity and remodeling are characteristic features of asthma. Interactions between the airway epithelium and environmental allergens are believed to be important in driving development of pathology, particularly because altered epithelial gene expression is common in individuals with asthma. Objectives: To investigate the interactions between a modified airway epithelium and a common aeroallergen in vivo. Methods: We used an adenoviral vector to generate mice overexpressing the transforming growth factor-b signaling molecule, Smad2, in the airway epithelium and exposed them to house dust mite (HDM) extract intranasally. Measurements and Main Results: Smad2 overexpression resulted in enhanced airway hyperreactivity after allergen challenge concomitant with changes in airway remodeling. Subepithelial collagen deposition was increased and smooth muscle hyperplasia was evident resulting in thickening of the airway smooth muscle layer. However, there was no increase in airway inflammation in mice given the Smad2 vector compared with the control vector. Enhanced airway hyperreactivity and remodeling did not correlate with elevated levels of Th2 cytokines, such as IL-13 or IL-4. However, mice overexpressing Smad2 in the airway epithelium showed significantly enhanced levels of IL-25 and activin A after HDM exposure. Blocking activin A with a neutralizing antibody prevented the increase in lung IL-25 and inhibited subsequent collagen deposition and also the enhanced airway hyperreactivity observed in the Smad2 overexpressing HDM-exposed mice. Conclusions: Epithelial overexpression of Smad2 can specifically alter airway hyperreactivity and remodeling in response to an aeroallergen. Moreover, we have identified novel roles for IL-25 and activin A in driving airway hyperreactivity and remodeling.

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“…Additionally, beta E expression was found and confirmed to be elevated in HepG2 cells as a consequence of phospholipidosis, a lipid storage disorder [91,92] . Expression of activin beta E was also significantly increased in the lung following airway inflammation [93] and in brains of rats infected with Borna disease virus [94] . Interestingly, a neuronal component has also been implied by recent work describing reduced anxiety-related behavior in mice overexpressing activin beta E [95] .…”

Section: Beta C and Beta Ementioning

confidence: 94%

Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

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Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.

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Activation of the TGF- β /Activin-Smad2 Pathway during Allergic Airway Inflammation

Cited by 118 publications

References 35 publications

Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells

Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells

Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Activins and follistatins: Emerging roles in liver physiology and cancer

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