Smad2 is Involved in Aggregatibacter actinomycetemcomitans-induced Apoptosis

Apoptosis is thought to contribute to the progression of periodontitis. It has been suggested that the apoptosis of epithelial cells may contribute to the loss of epithelial barrier function. Smad2, a downstream signaling molecule of TGF-β receptors (TGF-βRs), is critically involved in apoptosis in several cell types. However, the relationship between smad2 and bacteria-induced apoptosis has not yet been elucidated. It is possible that the regulation of apoptosis induced by periodontopathic bacteria may lead to novel preventive therapies for periodontitis. Therefore, in the present study, we investigated the involvement of smad2 phosphorylation in apoptosis of human gingival epithelial cells induced by Aggregatibacter actinomycetemcomitans ( Aa). Aa apparently induced the phosphorylation of smad2 in primary human gingival epithelial cells (HGECs) or the human gingival epithelial cell line, OBA9 cells. In addition, Aa induced phosphorylation of the serine residue of the TGF-β type I receptor (TGF-βRI) in OBA9 cells. SB431542 (a TGF-βRI inhibitor) and siRNA transfection for TGF-βRI, which reduced both TGF-βRI mRNA and protein levels, markedly attenuated the Aa-induced phosphorylation of smad2. Furthermore, the disruption of TGF-βRI signaling cascade by SB431542 and siRNA transfection for TGF-βRI abrogated the activation of cleaved caspase-3 expression and repressed apoptosis in OBA9 cells treated with Aa. Thus, Aa induced apoptosis in gingival epithelial cells by activating the TGF-βRI-smad2-caspase-3 signaling pathway. The results of the present study may suggest that the periodontopathic bacteria, Aa, activates the TGF-βR/smad2 signaling pathway in human gingival epithelial cells and induces apoptosis in epithelial cells, which may lead to new therapeutic strategies that modulate the initiation of periodontitis.

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Pro-inflammatory cytokine responses in human gingival epithelial cells after stimulation with cell wall extract of Aggregatibacter actinomycetemcomitans subtypes

Anaerobe ◽

10.1016/j.anaerobe.2017.08.001 ◽

2017 ◽

Vol 48 ◽

pp. 103-109 ◽

Cited By ~ 5

Author(s):

Nuntiya Pahumunto ◽

Pareena Chotjumlong ◽

Anupong Makeudom ◽

Suttichai Krisanaprakornkit ◽

Gunnar Dahlen ◽

...

Keyword(s):

Cell Wall ◽

Epithelial Cells ◽

Inflammatory Cytokine ◽

Aggregatibacter Actinomycetemcomitans ◽

Cytokine Responses ◽

Gingival Epithelial Cells ◽

Cell Wall Extract ◽

Human Gingival Epithelial Cells

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Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00074.2012 ◽

2012 ◽

Vol 303 (1) ◽

pp. E132-E143 ◽

Cited By ~ 16

Author(s):

Fang Zhao ◽

Fengjie Huang ◽

Mengxiong Tang ◽

Xiaoming Li ◽

Nina Zhang ◽

...

Keyword(s):

Signaling Pathway ◽

Cell Apoptosis ◽

Caspase 3 ◽

Biological Effects ◽

Cell Mass ◽

Type I ◽

Β Cells ◽

Β Cell ◽

Akt Phosphorylation ◽

Induced Apoptosis

We demonstrated previously that the activation of ALK7 (activin receptor-like kinase-7), a member of the type I receptor serine/threonine kinases of the TGF-β superfamily, resulted in increased apoptosis and reduced proliferation through suppression of Akt signaling and the activation of Smad2-dependent signaling pathway in pancreatic β-cells. Here, we show that Nodal activates ALK7 signaling and regulates β-cell apoptosis. We detected Nodal expression in the clonal β-cell lines and rodent islet β-cells. Induction of β-cell apoptosis by treatment with high glucose, palmitate, or cytokines significantly increased Nodal expression in clonal INS-1 β-cells and isolated rat islets. The stimuli induced upregulation of Nodal expression levels were associated with elevation of ALK7 protein and enhanced phosphorylated Smad3 protein. Nodal treatment or overexpression of Nodal dose- or time-dependently increased active caspase-3 levels in INS-1 cells. Nodal-induced apoptosis was associated with decreased Akt phosphorylation and reduced expression level of X-linked inhibitor of apoptosis (XIAP). Remarkably, overexpression of XIAP or constitutively active Akt, or ablation of Smad2/3 activity partially blocked Nodal-induced apoptosis. Furthermore, siRNA-mediated ALK7 knockdown significantly attenuated Nodal-induced apoptosis of INS-1 cells. We suggest that Nodal-induced apoptosis in β-cells is mediated through ALK7 signaling involving the activation of Smad2/3-caspase-3 and the suppression of Akt and XIAP pathways and that Nodal may exert its biological effects on the modulation of β-cell survival and β-cell mass in an autocrine fashion.

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