Tumor Necrosis Factor–α (TNF-α) Induces Upregulation of RhoA via NF-κB Activation in Cultured Human Bronchial Smooth Muscle Cells

Goto, Kumiko; Chiba, Yoshihiko; Sakai, Hiroyasu; Misawa, Miwa

doi:10.1254/jphs.09081fp

Cited by 20 publications

(22 citation statements)

References 40 publications

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“…In our previous study, the increase in the nuclear p65 was observed when cells were stimulated with 10 ng/mL of TNF-α for 30 min, and the increase in nuclear p65 induced by TNF-α was significantly inhibited by BMS-345541 in a concentration-dependent manner in hBSMCs [37]. Furthermore, TNF-α-induced increase in RhoA protein was inhibited by BMS-345541 [37].…”

Section: Resultsmentioning

confidence: 99%

The proximal STAT6 and NF-κB sites are responsible for IL-13- and TNF-α-induced RhoA transcriptions in human bronchial smooth muscle cells

Goto

Chiba

Matsusue

et al. 2010

Pharmacological Research

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RhoA protein is involved in the Ca2+ sensitization of bronchial smooth muscle (BSM) contraction, and an upregulation of RhoA in BSMs has been suggested in allergic bronchial asthma. However, the mechanism of upregulation of RhoA remains poorly understood. In the present study, the transcriptional regulation of human RhoA gene was investigated in cultured human BSM cells stimulated with IL-13 and TNF-α, both of which have an ability to upregulate RhoA protein. Luciferase-based assay showed that the RhoA promoter activity was augmented by both IL-13 and TNF-α. The deletion studies revealed a significant level of promoter activity between the 112 bp upstream and the transcription start site, which contains the STAT6 (78–70 bp upstream) and NF-κB (84–74 bp upstream) binding regions. The promoter activity was also decreased significantly by the mutations of these regions. Thus, the current study for the first time characterized the transcriptional regulation of the human RhoA gene. The findings also suggest that STAT6 and NF-κB are important for the upregulation of RhoA in human BSM induced by IL-13 and TNF-α, both of which are major cytokines in the pathogenesis of allergic bronchial asthma.

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Section: Resultsmentioning

confidence: 99%

The proximal STAT6 and NF-κB sites are responsible for IL-13- and TNF-α-induced RhoA transcriptions in human bronchial smooth muscle cells

Goto

Chiba

Matsusue

et al. 2010

Pharmacological Research

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“…The RhoA mRNA expression in human bronchial smooth muscle can also be induced by cytokines, such as IL-13 and TNF-α, and additionally, STAT6 and NF-κB are important for this up-regulation [34]. TNF-α can also induce the up-regulation of RhoA via NF-κB activation in cultured human bronchial smooth muscle cells [35]. This up-regulation mechanism of RhoA was mediated by GEFF-H1, as the siRNA-induced down-regulation of GEFF-H1 prevented the activation of the Rho pathway [36].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RhoA expression by adenovirus-mediated siRNA combined with TNF-α induced apoptosis of hepatocarcinoma cells

Yin

Zhao

Huang

et al. 2015

BME

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Abstract. Tumor necrosis factor-alpha (TNF-α) has been used as an effective treatment for Hepatocellular Carcinoma, however, inducing tumor cell apoptosis by TNF-α alone is still unsatisfactory. RhoA is highly expressed in hepatocarcinoma cells and can be activated by TNF-α. The activation of RhoA directly leads to a poor prognosis of HCC. Therefore, we propose to investigate the therapeutic effect of TNF-α together with RhoA siRNA. RhoA inhibition was accomplished by constructing a recombinant adenovirus that can efficiently express RhoA siRNA in HepG2 cells. The recombinant adenovirus AdshRNA-RhoA and AdU6-control were generated by adenovirus-mediated siRNA expression system. The inhibition effects were detected by RT-PCR in addition to immunoblot to quantify the decreased levels of RhoA expression, and the therapeutic effect for HCC was demonstrated by the proliferation and apoptosis ratios of HepG2 cells. The inhibition effects of RhoA by AdshRNA-RhoA were significant at both mRNA and protein levels: the transcription of RhoA mRNA decreased by 74.46%, and the expression of protein decreased by 76.48%. The proliferation rate of HepG2 cells detected by MTT showed that a treatment of AdshRNA-RhoA and TNF-α together could strengthen the suppression ability of TNF-α to HepG2 cells, resulting in approximately 14.2% more than those treated with only TNF-α. FCA and TUNEL assays results revealed that the combined treatment can induce apoptosis in approximately 52.14%-65% of the HepG2 cells, whereas this ratio in the TNF-α-alone group was only 21.91%-32%. Our results showed that AdshRNA-RhoA can efficiently enhance the TNF-α-induced apoptosis of hepatocarcinoma cells. This method might be a useful therapeutic route in HCC and other tumors.

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“…Commonly used TNFα concentrations with physiological effects are between 10–100 ng/ml [29], [30], [31]. We used concentration of 50 ng/ml for our studies.…”

Section: Discussionmentioning

confidence: 99%

Dual Regulation of Myocardin Expression by Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

Singh

Zheng

2014

PLoS ONE

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De-differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis, a chronic inflammatory disease involving various cytokines such as tumor necrosis factor-α (TNFα). Myocardin is a co-factor of serum response factor (SRF) and is considered to be the master regulator of VSMC differentiation. It binds to SRF and regulates the expression of contractile proteins in VSMCs. Myocardin is also known to inhibit VSMC proliferation by inhibiting the NF-κB pathway, whereas TNFα is known to activate the NF-κB pathway in VSMCs. NF-κB activation has also been shown to inhibit myocardin expression and smooth muscle contractile marker genes. However, it is not definitively known whether TNFα regulates the expression and activity of myocardin in VSMCs. The current study aimed to investigate the role of TNFα in regulating myocardin and VSMC function. Our studies showed that TNFα down-regulated myocardin expression and activity in cultured VSMCs by activating the NF-κB pathway, resulting in decreased VSMC contractility and increased VSMC proliferation. Surprisingly, we also found that TNFα prevented myocardin mRNA degradation, and resulted in a further significant increase in myocardin expression and activity in differentiated VSMCs. Both the NF-κB and p44/42 MAPK pathways were involved in TNFα regulation of myocardin, which further increased the contractility of VSMCs. These differential effects of TNFα on myocardin seemingly depended on whether VSMCs were in a differentiated or de-differentiated state. Taken together, our results demonstrate that TNFα differentially regulates myocardin expression and activity, which may play a key role in regulating VSMC functions.

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Tumor Necrosis Factor–α (TNF-α) Induces Upregulation of RhoA via NF-κB Activation in Cultured Human Bronchial Smooth Muscle Cells

Cited by 20 publications

References 40 publications

The proximal STAT6 and NF-κB sites are responsible for IL-13- and TNF-α-induced RhoA transcriptions in human bronchial smooth muscle cells

The proximal STAT6 and NF-κB sites are responsible for IL-13- and TNF-α-induced RhoA transcriptions in human bronchial smooth muscle cells

Inhibition of RhoA expression by adenovirus-mediated siRNA combined with TNF-α induced apoptosis of hepatocarcinoma cells

Dual Regulation of Myocardin Expression by Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

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