Dataset Information

Interleukin-22 is elevated in the atrium and plasma of patients with atrial fibrillation and increases collagen synthesis in transforming growth factor-?1-treated cardiac fibroblasts via the JNK pathway.

ABSTRACT: Our previous studies demonstrated that interleukin (IL)-22 is involved in cardiovascular diseases such as hypertension, cardiac fibrosis and aortic dissection. The purpose of the present study was to detect IL-22 expression in patients with atrial fibrillation (AF). Atrial tissue was collected from donors with sinus rhythm and patients with permanent AF, and the expression level of IL-22 and its receptors (IL-22R1 and IL-10R2) in both the left atrium (LA) and right atrium (RA) of each sample was detected. Blood samples were also obtained from donors with paroxysmal, persistent and permanent AF and from donors without AF history, and IL-22 levels were measured. In addition, the effects of IL-22 on collagen synthesis in TGF-?1-treated cardiac fibroblasts were investigated. IL-22R1, IL-10R2 and IL-22 expression was elevated in both the LA and RA in permanent AF patients. Elevated IL-22 expression positively correlated with the collagen areas and fibrosis marker levels in the atria of these patients. Plasma IL-22 levels were higher in AF patients compared with healthy donors and increased with increasing AF duration (from paroxysmal to persistent to permanent AF). A positive correlation was observed between IL-22 levels and TGF-?1 levels in AF patients. In vitro, recombinant mouse IL-22 treatment upregulated ?-SMA, collagen I and collagen III expression in TGF-?1-treated cardiac fibroblasts. These effects were reversed by SP600125, an inhibitor of the JNK pathway. To conclude, IL-22 levels are elevated in patients with AF and may exacerbate collagen synthesis in TGF-?1-induced cardiac fibroblasts. IL-22 may also influence AF by activating the JNK pathway.

SUBMITTER: Wu Y

PROVIDER: S-EPMC7388263 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Interleukin-22 is elevated in the atrium and plasma of patients with atrial fibrillation and increases collagen synthesis in transforming growth factor-β1-treated cardiac fibroblasts via the JNK pathway.

Wu Yongxin Y Tan Lihua L Shi Lei L Yang Zicong Z Xue Yan Y Zeng Tao T Shi Ying Y Lin Yingzhong Y Liu Ling L

Experimental and therapeutic medicine 20200521 2

Our previous studies demonstrated that interleukin (IL)-22 is involved in cardiovascular diseases such as hypertension, cardiac fibrosis and aortic dissection. The purpose of the present study was to detect IL-22 expression in patients with atrial fibrillation (AF). Atrial tissue was collected from donors with sinus rhythm and patients with permanent AF, and the expression level of IL-22 and its receptors (IL-22R1 and IL-10R2) in both the left atrium (LA) and right atrium (RA) of each sample was ...[more]

PMID: 32742343

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Project description:Functional cytokine networks have been poorly characterized in systemic sclerosis (SSc). While interleukin-17A (IL-17A) is increased in SSc skin and other organs, its role is still debated, particularly considering fibrogenesis. We uncover here a dual function of IL-17A in the presence of transforming growth factor-? 1 (TGF-?), the master pro-fibrotic cytokine. In the one hand, we report an unexpected synergic activity resulting in enhanced production of IL-6 by dermal fibroblasts; in the other hand, a substantial inhibition of type I collagen (col-I) production. IL-17A or TGF-? enhanced the production of IL-6 by 8- to 16-folds when compared to control in healthy donors (HD) and SSc cultures. However, the joint presence of IL-17A and TGF-? resulted in robustly exuberant responses with levels of IL-6 up to 100-folds higher than those observed in untreated cells. Inhibition of NF?B signaling pathway preferentially inhibited the production of IL-6 driven by IL-17A in HD fibroblasts, while inhibition of PI3K preferentially inhibited the production of IL-6 driven by TGF-?. Interestingly, when p38 MAPK was inhibited, substantial reduction of IL-6 production was observed for both IL-17A and TGF-?. Consistently with the inhibition experiments, the combined stimulation of fibroblasts by IL-17A and TGF-? resulted in 1.8-fold increase in p38 MAPK phosphorylation (P?=?0.025), when compared to levels of phosphorylated p38 MAPK induced by IL-17A alone. Furthermore, the enhanced phosphorylation of p38 MAPK in the joint presence of IL-17A and TGF-? was unique among the signaling molecules we examined. As expected, TGF-? induced SMAD2 phosphorylation and col-I production. However, in fibroblasts cultured in the joint presence of TGF-? and IL-17A, SMAD2 phosphorylation was decreased by 0.6-folds (P?=?0.022) when compared to that induced by TGF-? alone. Remarkably, in this condition, the production of col-I and fibronectin was significantly decreased in both HD and SSc. Thus, IL-17A and TGF-? reciprocally influence each other effector functions in fibroblasts. Intracellular molecular switches may favor synergic or antagonistic activities, which are revealed by specific readouts. The implications of these data in the context of SSc are far reaching, particularly in terms of therapeutic approaches since IL-6, IL-17A, and TGF-? are all putative targets of treatment.

Project description:ObjectiveBeta 1-adrenergic receptor autoantibodies (β1ARAbs) have been identified as a pathogenic factor in atrial fibrillation (AF), but the underlying pathogenetic mechanism is not well understood. We assessed the hypothesis that elevated β1ARAb levels increase AF susceptibility by promoting atrial fibrosis.MethodsA total of 70 patients with paroxysmal AF were continuously recruited. The serum levels of β1ARAb and circulating fibrosis biomarkers were analyzed by ELISA. Linear regression was used to examine the correlations of β1ARAb levels with left atrial diameter (LAD) and circulating fibrosis biomarker levels. Furthermore, we established a rabbit β1ARAb overexpression model. We conducted electrophysiological studies and multielectrode array recordings to evaluate the atrial effective refractory period (AERP), AF inducibility and electrical conduction. AF was defined as irregular, rapid atrial beats > 500 bpm for > 1000 ms. Echocardiography, hematoxylin and eosin staining, Masson's trichrome staining, and picrosirius red staining were performed to evaluate changes in atrial structure and detect fibrosis. Western blotting and PCR were used to detect alterations in the protein and mRNA expression of TGF-β1, collagen I and collagen III.ResultsPatients with a LAD ≥ 40 mm had higher β1ARAb levels than patients with a smaller LAD (8.87 ± 3.16 vs. 6.75 ± 1.34 ng/mL, P = 0.005). β1ARAb levels were positively correlated with LAD and circulating biomarker levels (all P < 0.05). Compared with the control group, the rabbits in the immune group showed the following: (1) enhanced heart rate, shortened AERP (70.00 ± 5.49 vs. 96.46 ± 3.27 ms, P < 0.001), increased AF inducibility (55% vs. 0%, P < 0.001), decreased conduction velocity and increased conduction heterogeneity; (2) enlarged LAD and elevated systolic dysfunction; (3) significant fibrosis in the left atrium identified by Masson's trichrome staining (15.17 ± 3.46 vs. 4.92 ± 1.72%, P < 0.001) and picrosirius red staining (16.76 ± 6.40 vs. 4.85 ± 0.40%, P < 0.001); and (4) increased expression levels of TGF-β1, collagen I and collagen III.ConclusionOur clinical and experiential studies showed that β1ARAbs participate in the development of AF and that the potential mechanism is related to the promotion of atrial fibrosis.

Dataset Information

Interleukin-22 is elevated in the atrium and plasma of patients with atrial fibrillation and increases collagen synthesis in transforming growth factor-?1-treated cardiac fibroblasts via the JNK pathway.

Publications

Interleukin-22 is elevated in the atrium and plasma of patients with atrial fibrillation and increases collagen synthesis in transforming growth factor-β1-treated cardiac fibroblasts via the JNK pathway.

Similar Datasets

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