β2‐adrenergic stimulation induces interleukin‐6 by increasing Arid5a, a stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts

Tanaka, Shota; Imaeda, Atsuki; Matsumoto, Kotaro; Maeda, Makiko; Obana, Masanori; Fujio, Yasushi

doi:10.1002/prp2.590

Cited by 13 publications

(10 citation statements)

References 33 publications

(46 reference statements)

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“…Similarly, the efforts of Masuda et al revealed that Arid5a possesses the ability to promote cytokine production and control the half-life of pro-inflammatory factors, including IL-6 and STAT3, in activated macrophages, as well as T cells [ 26 ]. On the other hand, up-regulation of Arid5a induced by β2-adrenergic stimulation was previously associated with elevated IL-6 levels, thereby enhancing inflammation in cardiac fibroblasts [ 27 ]. Meanwhile, Arid5a-induced selective stabilization of STAT3 is known to influence the fate of CD4 + T cells [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Blockade of the Arid5a/IL-6/STAT3 axis underlies the anti-inflammatory effect of Rbpjl in acute pancreatitis

Fang

Sun

et al. 2022

Cell Biosci

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Background The microarray data analysis predicted that Rbpjl is poorly expressed in acute pancreatitis (AP). Activated IL-6/STAT3 signaling is further known to contribute to the progression of AP through immune regulation, and both IL-6 and STAT3 were bioinformatically predicted to interact with Arid5a. Accordingly, we aimed to investigate the potential involvement of the Arid5a/IL-6/STAT3 axis in the regulatory role of Rbpjl in the inflammation of AP. Methods Pancreatic acinar cells were exposed to lipopolysaccharide (LPS) to induce the pancreatic cell damage, and mice were subjected to supramaximal cerulein stimulation to induce AP. Expression patterns of Rbpjl and the Arid5a/IL-6/STAT3 axis were measured in mouse and cell models. Their expression was further manipulated to explore their effects on pancreatic cell injury and inflammation, as reflected by cell viability and apoptosis as well as reactive oxygen species (ROS) accumulation and proinflammatory cytokine secretion. Moreover, ChIP, EMSA, and dual-luciferase reporter assays were carried out to identify the interactions between Rbpjl and Arid5a. Results Rbpjl was found to be down-regulated in pancreatic tissues of AP mice and LPS-induced pancreatic acinar cells, while re-expression of Rbpjl led to enhanced cell viability, suppressed LPS-induced inflammation and ROS accumulation, and alleviation of AP-induced damage. Mechanistically, Rbpjl could bind to the promoter region of Arid5a and down-regulated its expression, thus repressing the activation of the IL-6/STAT3 signal axis. Furthermore, Rbpjl impaired Arid5a-dependent IL-6/STAT3 activation, hence alleviating pancreatic acinar cell inflammation. Furthermore, these effects were validated with in vivo experiments. Conclusion Collectively, our findings highlight that Rbpjl attenuates AP by down-regulating Arid5a and inactivating the IL-6/STAT3 pathway.

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Section: Discussionmentioning

confidence: 99%

Blockade of the Arid5a/IL-6/STAT3 axis underlies the anti-inflammatory effect of Rbpjl in acute pancreatitis

Fang

Sun

et al. 2022

Cell Biosci

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“…Furthermore, GRK2 phosphorylates activated β-ARs to decouple G protein, decreasing the level of cAMP and then aggravates cardiac myocytes death. Recent study suggests inhibiting GRK2 in the cardiac fibroblasts (CF) could decrease fibrosis and fibrotic gene expression ( 48 ). These findings emphasize that a complex interaction exists among GRK2 and the AC/cAMP/PKA signaling pathway during the progression of fibrosis.…”

Section: Relationship Between Grk2 and Fibrosis-associated Pathwaysmentioning

confidence: 99%

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Shan

et al. 2022

Front. Immunol.

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G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.

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“…Thus, inhibition of production of proinflammatory cytokines may be a useful strategy for cardiac remodeling. A recent study suggested that β2-adrenergic stimulation induces Arid5a, which further post-transcriptionally upregulates the expression of Il6 mRNA through the cAMP/PKA/CREB pathway in adult cardiac fibroblasts, and indicates that the β2AR/Arid5a/IL6 axis may be a therapeutic target to prevent cardiac inflammation ( 42 ).…”

Section: Arid5a-mediated Regulation Of Inflammatory Genesmentioning

confidence: 99%

Recent Advances in the Role of Arid5a in Immune Diseases and Cancer

Nyati

Kishimoto

2022

Front. Immunol.

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AT-rich interactive domain 5a (Arid5a) is a nucleic acid binding protein. In this review, we highlight recent advances in the association of Arid5a with inflammation and human diseases. Arid5a is known as a protein that performs dual functions. In in vitro and in vivo studies, it was found that an inflammation-dependent increase in Arid5a expression mediates both transcriptional and post-transcriptional regulatory effects that are implicated in immune regulation and cellular homeostasis. A series of publications demonstrated that inhibiting Arid5a augmented several processes, such as preventing septic shock, experimental autoimmune encephalomyelitis, acute lung injury, invasion and metastasis, immune evasion, epithelial-to-mesenchymal transition, and the M1-like tumor-associated macrophage (TAM) to M2-like TAM transition. In addition, Arid5a controls adipogenesis and obesity in mice to maintain metabolic homeostasis. Taken together, recent progress indicates that Arid5a exhibits multifaceted, both beneficial and detrimental, roles in health and disease and suggest the relevance of Arid5a as a potential therapeutic target.

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β2‐adrenergic stimulation induces interleukin‐6 by increasing Arid5a, a stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts

Cited by 13 publications

References 33 publications

Blockade of the Arid5a/IL-6/STAT3 axis underlies the anti-inflammatory effect of Rbpjl in acute pancreatitis

Blockade of the Arid5a/IL-6/STAT3 axis underlies the anti-inflammatory effect of Rbpjl in acute pancreatitis

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Recent Advances in the Role of Arid5a in Immune Diseases and Cancer

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