TGF-β induces p65 acetylation to enhance bacteria-induced NF-κB activation

Ishinaga, Hajime; Jono, Hirofumi; Lim, Jae Hyang; Kweon, Soo Mi; Xu, Haodong; Ha, Un-Hwan; Xu, Haidong; Koga, Tomoaki; Yan, Chen; Feng, Xin; Chen, Lin Feng; Li, Jian Dong

doi:10.1038/sj.emboj.7601546

Cited by 86 publications

(80 citation statements)

References 49 publications

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“…Moreover, inhibition of PKA pathway by H89 could abolish the cAMP-mediated aromatase induction through up-regulating brca1 expression (44). Similar to our study, a number of previous reports support the possibility that PKA signaling contributes to the constitutive NF-B activation (45)(46)(47). In this study, we demonstrated that NF-B inhibitor BAY11-7082 repressed MDA-MB231 cell proliferation by blocking IKK, and PKA inhibitor H89 further augmented this inhibitory action (Fig.…”

Section: Discussionsupporting

confidence: 78%

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

Gao

Hibi

Cueno

et al. 2010

Journal of Biological Chemistry

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NF-B is an inducible transcriptional factor for the expression of multiple genes involved in immunoinflammatory responses, cell proliferation, and survival, thus playing crucial roles in the pathogenesis of many diseases, including cancer, leukemia, and autoimmune diseases (1-4). NF-B primarily exists as the heterodimer consisting of p65 and p50 in the cytoplasm and is sequestered by binding to its inhibitory protein IB (5). Upon signaling, such as by tumor necrosis factor ␣ (TNF␣), IB is phosphorylated and is followed by proteasomemediated degradation, which liberates NF-B to the nucleus thereby activating the target genes.PKA exists in the cytoplasm as an inactivated tetramer holoenzyme composed of dimer catalytic subunits and dimer regulatory subunits, which dissociate upon elevation of cAMP (6 -10). PKAc is also predominantly involved in the IB-NF-B complex in the cytoplasm, and IB sequesters PKAc by masking its catalytic domain (11). Following a variety of extracellular stimuli such as TNF␣, IB is phosphorylated by IKK 2 and degraded by the 26 S proteasome (12, 13). As a consequence, the p65/p50 heterodimer complex is liberated, and the catalytic center of PKAc is exposed, enabling activated PKAc to phosphorylate p65 at 15). This PKA-dependent phosphorylation of p65 facilitates the recruitment of transcription coactivator CBP and DNA binding activity of p65; therefore, activation of PKA augments NF-B-dependent gene expression, and PKAc signaling is considered to up-regulate . With regard to the role of PKAc in NF-B signaling, some claimed that cAMP-dependent PKA activation down-regulated NF-B-dependent transcription by changing its DNA binding ability (18,19), modifying the transactivation domain of p65 (20), or blocking the degradation of IB proteins (21,22).In our previous report, we identified AKIP1 as a novel p65-interacting protein (23). AKIP1 was initially found in breast cancer cells (24) in which it facilitated the nuclear translocation of PKAc (25). We found that AKIP1 appears to serve as a molecular bridge between p65 and PKAc, promoting their interaction and subsequent p65 phosphorylation at Ser-276, thus enhancing NF-B signaling (23). Because NF-B is constitutively activated in some breast cancer cells, endowing them with resistance to apoptosis (26 -28), we hypothesized that the effect of PKA in NF-B cascade is associated with AKIP1 and could be modulated by AKIP1 in a cell type-dependent fashion.In this study, we further investigate the role of PKA in regulating NF-B-dependent transcription in various cell lines with different expression levels of endogenous AKIP1. We provide evidence that in minimal AKIP1-expressing cell lines, elevation of cAMP decreased p65-PKA binding and p65 phosphorylation at Ser-276, which eventually leads to down-regulation of the NF-B-dependent transcription. In contrast, in breast cancer cell lines MDA-MB231 and MCF7 with high AKIP1 expression, the PKA-activating agents increased p65-PKA binding and its phosphorylation and up-regulated the NF-B-dependent transcriptio...

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Section: Discussionsupporting

confidence: 78%

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

Gao

Hibi

Cueno

et al. 2010

Journal of Biological Chemistry

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“…78,79 (v) It has been clearly demonstrated that the action of TGF-b is induced through the activation of NF-kB. 25,26,75,76,80,81 At the same time, it has been reported that NF-kB activation induces TGF-b production. [82][83][84] Thus, there is a potential positive feedback mechanism between TGF-b production and NF-kB activation that enhances the fibrotic process.…”

Section: Discussionmentioning

confidence: 97%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

119

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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“…C57BL/6 mice at 8 weeks of age were used, as previously described (20). Under anesthesia, mice were intratracheally inoculated with LPS (Escherichia coli serotype 055:B5, 2 μg per mouse; Sigma) in 50 μL of PBS vehicle or TNF-α (500 ng per mouse) or with same volume of saline as control for 6 h. Vinpocetine (10 mg/kg of body weight) or an equal volume of vehicle control was administered via an i.p.…”

Section: Methodsmentioning

confidence: 99%

“…To confirm if vinpocetine also inhibits inflammatory responses in vivo, we evaluated the effects of vinpocetine on lung inflammation induced by intratracheal inoculation with LPS or TNF-α for 6 h, a wellestablished mouse model of lung inflammation (20). As shown in Fig.…”

Section: Vinpocetine Inhibits Monocyte Adhesion Of Huvecs and Chemotamentioning

confidence: 99%

Vinpocetine inhibits NF-κB–dependent inflammation via an IKK-dependent but PDE-independent mechanism

Jeon

Aizawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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206

180

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Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-α-induced NF-κB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-α-or LPS-induced up-regulation of proinflammatory mediators, including TNF-α, IL-1β, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-α-or LPSinduced lung inflammation. Interestingly, vinpocetine inhibits NF-κB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca 2+ regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.vinpocetine | inflammation | NF-κB | IKK

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TGF-β induces p65 acetylation to enhance bacteria-induced NF-κB activation

Cited by 86 publications

References 49 publications

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Vinpocetine inhibits NF-κB–dependent inflammation via an IKK-dependent but PDE-independent mechanism

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