Nicotine stimulates IL‐6 expression by activating the AP‐1 and STAT‐3 pathways in human endothelial EA.hy926 cells

Ung, Trong Thuan; Nguyen, Thi Phuong; Lian, Sen; Li, Shinan; Xia, Yong; Kim, Nam Ho; Jung, Young Do

doi:10.1002/jcb.27837

Cited by 20 publications

(10 citation statements)

References 49 publications

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“…Indeed, IgG4-RD RI, rather than serum IgG4, is closely related to disease activity (23,38), indicating that the increased level of IL-6 was directly correlated with disease activity and was also involved in the development of IgG4-RD. As a critical pro-inflammatory factor, IL-6 is produced by both immune cells, as well as various types of tissue cells (e.g., fibroblasts, epithelial cells, and keratinocytes) under the stimulation of IL-1, TNF-α, PDGF, virus, doublestranded RNA, and c-AMP, and subsequently promotes the development of inflammatory and autoimmune diseases (54)(55)(56)(57)(58). However, whether tissue cells in the affected organs of IgG4-RD can produce IL-6 remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…As a critical pro-inflammatory factor, IL-6 is produced by both immune cells, as well as various types of tissue cells (e.g., fibroblasts, epithelial cells, and keratinocytes) under the stimulation of IL-1, TNF-α, PDGF, virus, double-stranded RNA, and c-AMP, and subsequently promotes the development of inflammatory and autoimmune diseases ( 54 – 58 ). However, whether tissue cells in the affected organs of IgG4-RD can produce IL-6 remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

Chen

Cui

et al. 2020

Front. Immunol.

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Background: The remarkable mechanisms of storiform fibrosis and the formation of high levels of IgG4 with a pathogenic germinal center (GC) in the inflammatory tissue of IgG4-RD remains unknown and may be responsible for the unsatisfactory therapeutic effect on IgG4-related diseases when using conventional therapy. Objectives: To investigate the mechanisms of interleukin 6 (IL-6) inducing fibroblasts to produce cytokines for pathogenic GC formation in the development of IgG4-related disease (IgG4-RD). Methods: The clinical data and laboratory examinations of 56 patients with IgG4-RD were collected. IL-6 and IL-6R expression in the serum and tissues of patients with IgG4-RD and healthy controls were detected by ELISA, immunohistochemistry, and immunofluorescence. Human aorta adventitial fibroblasts (AAFs) were cultured and stimulated with IL-6/IL-6 receptor (IL-6R). The effect of IL-6/IL-6R on AAFs was determined by Luminex assays. Results: The serum IL-6 and IL-6R levels were elevated in active IgG4-RD patients and IL-6 was positively correlated with the disease activity (e.g., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and IgG4-RD responder index). IL-6 and IL-6R expression in the tissue lesions of IgG4-related retroperitoneal fibrosis and IgG4-related sialadenitis patients were also significantly higher than that in the normal tissues. In addition, there is a relative abundance of myofibroblasts as well as IgG4 + plasma cells in the tissues of IgG4-related retroperitoneal fibrosis. α-SMA and B cell differentiation cytokines (i.e., B cell activating factor), and α-SMA and T follicular helper (Tfh) cell differentiation cytokines (e.g., IL-7, IL-12, and IL-23) were co-expressed in the local lesions. In vitro, IL-6/IL-6R significantly promoted the production of B cell activating factor, IL-7, IL-12, and IL-23 in AAFs in a dose-dependent manner. This effect was partially blocked by JAK1, JAK2, STAT3, and Akt inhibitors, respectively. Conclusions: In vitro IL-6/IL-6R trans-signaling in fibroblasts releases Tfh and B cell differentiation factors partially via the JAK2/STAT3, JAK1/STAT3, and JAK2/Akt Zongfei et al. IL-6 and Fibroblast Induced IgG4-RD pathways, which may be linked to the pathogenesis of IgG4-RD. This indicated that IL-6 and fibroblasts may be responsible for GC formation and fibrosis in the development of IgG4-RD. Blocking IL-6 with JAK1/2 inhibitors or inhibiting fibroblast proliferation might be beneficial for IgG4-RD treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

Chen

Cui

et al. 2020

Front. Immunol.

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“…Periodontitis and diabetes have raised pro‐inflammatory cytokine levels, comprising TNF‐α, interferon‐γ (INF‐γ), IL‐1β, IL‐6, and interleukin‐17 (IL‐17) 25,26 . IL‐6 has been the most investigated among them and could involve in endothelial dysfunction by stimulating adhesion molecule and cytokine levels, migration, and adhesion in vascular smooth muscle cells and endothelium 27–29 . From this, it is found that IL‐6 and VCAM‐1 were upregulated in vascular walls in diabetes with periodontitis.…”

Section: Discussionmentioning

confidence: 99%

Periodontitis exacerbates endothelial dysfunctions partly via endothelial‐mesenchymal transition in streptozotocin‐induced diabetes rats

Yang

Cheng

et al. 2022

J of Periodontal Research

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Objectives Periodontal infections are related to the expansion of diabetes cardiovascular problems. However, the pathological process and probable mechanism remain unexplained. This study investigated the impact of periodontitis on streptozotocin (STZ)‐induced diabetes rats' carotid artery. Methods We randomized 24 Sprague‐Dawley (SD) rats into four groups: control, chronic periodontitis (CP), diabetes mellitus (DM), and DM +CP groups. Fasting blood glucose (FBG) and hemoglobin A1c (HBA1c) were measured to verify the establishment of the DM model. After euthanasia, the maxillary was collected for further studies like hematoxylin‐eosin (HE), Masson staining, and micro‐computed tomography (micro‐CT) analysis. Immunofluorescence (IF) staining was used to detect endothelial‐mesenchymal transition (EndMT)‐related markers in carotid artery wall. We further used ELISA and quantitative real‐time PCR to investigate the effect of high glucose (HG) and Porphyromonas gingivalis lipopolysaccharide (P.g‐LPS) on human umbilical vein endothelial cells (HUVECs). Results Compared with DM and CP groups, bone resorption and pathological changes of the vascular wall were the most serious in the DM+CP group. The vascular wall of the DM+CP group had a higher level of interleukin (IL)‐6 and vascular cell adhesion molecule 1 (VCAM‐1). The carotid artery vascular wall of the DM+CP group contained more cells that expressed both mesenchymal and endothelial cell markers, along with elevated transcription factor levels. Furthermore, P.g‐LPS and HG upregulated the inflammatory cytokines expression and caused phenotypic changes of HUVECs in vitro. Conclusion Periodontitis exacerbates endothelial dysfunctions partly via endothelial‐mesenchymal transition in STZ‐induced diabetes rats.

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“… 52–54 On the other hand, nicotine stimulates increased expression of IL-6 through the p-38 MAPK/AP-1 and ROS/STAT-3 signalling pathways that trigger endothelial injury. 15 , 55 …”

Section: Discussionmentioning

confidence: 99%

Detection of Vascular Inflammation and Oxidative Stress by Cotinine in Smokers: Measured Through Interleukin-6 and Superoxide Dismutase

Kumboyono¹,

Chomsy²,

Hakim³

et al. 2022

IJGM

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Purpose Smoking is a significant risk factor in developing cardiovascular disease pathogenesis through oxidative stress and inflammation mechanisms. This study used cotinine as a biomarker of nicotine exposure levels in the body, which was associated with levels of Interleukin-6 (IL-6) and Superoxide Dismutase (SOD) as markers of oxidative stress and vascular inflammation. The research aimed to analyze the effect of cotinine levels on the expression of IL-6 and SOD. Methods This study used a cross-sectional design on 200 subjects, consisting 100 smokers and 100 non-smokers. Cotinine levels, IL-6 expression, and SOD were measured from the blood serum of each subject using the Enzyme-Linked Immunosorbent Assay (ELISA) method. Then the data were analyzed using Generalized Structured Component Analysis (GSCA). Results There was a significant effect of cotinine levels on the reduction of SOD mediated by IL-6 (CR = 4.006). Cotinine levels also increased IL-6 mediated by SOD (CR = 4.292). The structural model shows that higher cotinine levels will increase IL-6 expression, and conversely, SOD expression will decrease. Conclusion High cotinine levels cause an increase in the inflammatory process and oxidative stress in the vasculature of smokers, which is characterized by high IL-6 expression and low SOD expression.

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Nicotine stimulates IL‐6 expression by activating the AP‐1 and STAT‐3 pathways in human endothelial EA.hy926 cells

Cited by 20 publications

References 49 publications

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

Periodontitis exacerbates endothelial dysfunctions partly via endothelial‐mesenchymal transition in streptozotocin‐induced diabetes rats

Detection of Vascular Inflammation and Oxidative Stress by Cotinine in Smokers: Measured Through Interleukin-6 and Superoxide Dismutase

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