IL-35 subunit EBI3 alleviates bleomycin-induced pulmonary fibrosis via suppressing DNA enrichment of STAT3

Chen, Donghong; Zheng, Guofeng; Yang, Qing; Li, Luo; Shen, Jinglian

doi:10.1186/s12931-021-01858-x

Cited by 5 publications

(5 citation statements)

References 40 publications

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“…It would be interesting to investigate whether IL-35 can also regulate TGF-β binding or signalling. In contrast to our BAL findings, there are reports showing a higher expression of IL-35 subunit EBI3 on PBMCs from F-ILD patients [28] and serum IL-35 concentration, that are similar in scleroderma patients with pulmonary fibrosis and in healthy donors [32], and a positive correlation between IL-35 and TGF-β in plasma from patients with vascular diseases [33,34]. These apparent contradictions with our results are probably due to the determination of cytokine concentration in different compartments.…”

Section: Discussioncontrasting

confidence: 99%

“…This finding is in line with other studies [27]. In addition, an inhibitory function of IL‐35 in pulmonary fibrosis has been suggested in a mouse lung fibrotic model [28]. In the same report, using epithelium lung cell cultures, IL‐35 was able to activate STAT1 and STAT4.…”

Section: Discussionsupporting

confidence: 89%

“…In the same report, using epithelium lung cell cultures, IL‐35 was able to activate STAT1 and STAT4. These transcription factors inhibit the overexpression of fibrotic and extracellular matrix‐associated genes [28]. Here, higher concentrations of both TGF‐β and IL‐17 in BAL from F patients were also found.…”

Section: Discussionmentioning

confidence: 69%

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The immunoregulatory role of IL‐35 in patients with interstitial lung disease

et al. 2022

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Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF‐β and IL‐35, a recently identified heterodimeric cytokine that belongs to the IL‐12 cytokine family. However, the effect of regulatory IL‐35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL‐35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL‐35 and different profibrotic cytokines in fibrotic (F‐ILD) and non‐fibrotic (NF‐ILD) patients by ELISA were compared to that of intracellular IL‐35 and IL‐17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL‐35 (rIL‐35) and TGF‐β (rTGF‐β), which were evaluated by flow cytometry. We observed that BAL concentration of IL‐35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF‐β (p < 0.001) and IL‐17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL‐35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL‐17 + CD4+ T cells (p < 0.001). The percentage of IL‐35 + CD4+ T cells correlated positively with BAL concentration of IL‐35 (p = 0.02), but correlated negatively with BAL concentrations of IL‐17 (p = 0.007) and TGF‐β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF‐β: IL‐35 ratio of 1:4, an enhanced percentage of IL‐35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL‐17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL‐35 to the BAL from F patients until a 1:4 ratio of TGF‐β: IL‐35 was reached, a significantly increased percentage of IL‐35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL‐17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL‐35 may induce an anti‐fibrotic response, regulating the effect of TGF‐β and the inflammatory response on CD4+ T cells. In addition, the TGF‐β: IL‐35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 89%

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The immunoregulatory role of IL‐35 in patients with interstitial lung disease

et al. 2022

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“…A combination therapy of Tanshinone IIA and Puerarin for IPF was proposed to alleviate IPF, and IL-6-JAK2-STAT3/STAT1 is the key mechanism of the combination therapy. In a bleomycin-induced pulmonary fibrosis mice model, IL-35 activated STAT1 and STAT4, which in turn suppressed DNA enrichment of STAT3 and inhibited the fibrosis process ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Proteome, Lysine Acetylome, and Succinylome Identify Posttranslational Modification of STAT1 as a Novel Drug Target in Silicosis

Zhang,

Wang,

Sun

et al. 2024

Molecular & Cellular Proteomics

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“…Furthermore, this decrease in EBI3 may also contribute to the induction of IL-17 [ 40 ]. In addition, bleomycin-induced animal models have shown decreased levels of EBI3 in lung and skin fibrosis, and the supplementation of EBI3 has inhibited this fibrotic condition [ 40 , 41 ]. Second, we could not analyze the role of IL-35 in the monocytes from the patients.…”

Section: Discussionmentioning

confidence: 99%

Impaired Regulation by IL-35 in Systemic Sclerosis

Osuna-Gómez

Castellví

Mulet

et al. 2023

IJMS

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This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, p < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β (p < 0.001) and IL-17 (p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, p < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, p < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, p < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, p < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, p < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, p < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β (p < 0.001), while there was a negative correlation between mRSS and IL-35 (p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, p < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.

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IL-35 subunit EBI3 alleviates bleomycin-induced pulmonary fibrosis via suppressing DNA enrichment of STAT3

Cited by 5 publications

References 40 publications

The immunoregulatory role of IL‐35 in patients with interstitial lung disease

The immunoregulatory role of IL‐35 in patients with interstitial lung disease

Proteome, Lysine Acetylome, and Succinylome Identify Posttranslational Modification of STAT1 as a Novel Drug Target in Silicosis

Impaired Regulation by IL-35 in Systemic Sclerosis

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