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

Osuna-Gómez, Rubén; Barril, Silvia; Mulet, Maria; Atenza, Carlos Zamora; Millan‐Billi, Paloma; Pardessus, Ana; Brough, Douglas E.; Sabzevari, Helen; Semnani, Roshanak Tolouei; Castillo, Diego; Vidal, Sílvia

doi:10.1111/imm.13596

Cited by 6 publications

(10 citation statements)

References 51 publications

(56 reference statements)

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“…Based on the described mechanisms in this manuscript, high levels of IL-35 likely regulate systemic inflammation, shifting toward a limited SSc development. Given that IL-35 has been reported to regulate collagen and TGF-β expression in other rheumatic diseases, IL-35 may play a protective role in SSc pathogenesis [ 23 , 32 ]. Plasmatic IL-35, compared to other published biomarkers, is easy to obtain via non-invasive techniques, as are its dynamics, and it can be associated with severity and classification regardless of the received treatment.…”

Section: Discussionmentioning

confidence: 99%

“…For cytokine production, the PBMCs from HDs and SSc patients were cultured in 96 well-plates with complete RPMI 1640 and stimulated with dynabeads human T-activator CD3/CD28, in the absence or presence of 100 ng/mL of recombinant IL-35 (rIL-35; Enzo Life Sciences, Farmingdale, NY, USA) for 72 h in 5% CO 2 at 37 °C, as previously reported in our laboratory [ 23 ]. The supernatants were collected and stored at −20 °C to determine their cytokine concentration, as described below.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, a differential TCR signal strength generates distinct effector IL-10+ and IL-35+ Treg cell subsets with synergistic functions for controlling autoimmunity [ 20 ]. In line with IL-35 mechanisms, its levels are lower in patients with active autoimmunity disease (systemic lupus erythematosus, rheumatoid arthritis, and autoimmune interstitial lung disease) than those with inactive disease [ 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impaired Regulation by IL-35 in Systemic Sclerosis

Osuna-Gómez

Castellví

Mulet

et al. 2023

IJMS

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“…Interleukin 35 (IL-35) is a cytokine which is considered to have anti-fibrotic and anti-inflammatory effects by affecting interleukin 17 (IL-17) production. IL-35 also prevents the phosphorylation of Smad3, a downstream cascade of transforming growth factor (TGF-b) signaling, thus blocking TGF-b binding to its receptor and preventing the differentiation of T helper 17 (Th17) cells [ 68 ]. In a recent study of cytokines in BALF of patients with ILDs of various etiologies (fibrotic and non-fibrotic), the BALF concentration of IL-35 was lower in fibrotic ILDs and negatively associated with BALF concentrations of TGF-b.…”

Section: Biomarkers For Acute Exacerbations Of Ipfmentioning

confidence: 99%

Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers

Drakopanagiotakis

Markart

Steiropoulos

2023

IJMS

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Interstitial lung diseases (ILDs) are a large group of pulmonary disorders characterized histologically by the cardinal involvement of the pulmonary interstitium. The prototype of ILDs is idiopathic pulmonary fibrosis (IPF), an incurable disease characterized by progressive distortion and loss of normal lung architecture through unchecked collagen deposition. Acute exacerbations are dramatic events during the clinical course of ILDs, associated with high morbidity and mortality. Infections, microaspiration, and advanced lung disease might be involved in the pathogenesis of acute exacerbations. Despite clinical scores, the prediction of the onset and outcome of acute exacerbations is still inaccurate. Biomarkers are necessary to characterize acute exacerbations better. We review the evidence for alveolar epithelial cell, fibropoliferation, and immunity molecules as potential biomarkers for acute exacerbations of interstitial lung disease.

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“…Second, cytokine levels have been shown to be elevated in many patients with ILD, thus suggesting that they may also be involved in the development and progression of this condition. In fact, ILD is characterized by alveolar and interstitial inflammation, and the role of cytokines in the pathogenesis of ILD has been known for some time [ 19 , 20 ]. Nevertheless, cytokines have received little attention in RA-ILD, with the result that our knowledge is very limited.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Biomarkers in the Diagnosis and Prognosis of Rheumatoid Arthritis–Associated Interstitial Lung Disease

Mena-Vázquez

Godoy-Navarrete

Lisbona-Montañez

et al. 2023

IJMS

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Objectives: to identify inflammatory factors and soluble cytokines that act as biomarkers in the diagnosis and prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods: we performed a nested prospective observational case–control study of patients with RA-ILD matched by sex, age, and time since the diagnosis of RA. All participants underwent pulmonary function testing and high-resolution computed tomography. ILD was defined according to the criteria of the American Thoracic Society/European Respiratory Society; the progression of lung disease was defined as the worsening of FVC > 10% or DLCO > 15%. Inflammation-related variables included the inflammatory activity measured using the DAS28-ESR and a multiplex cytokine assay. Two Cox regression models were run to identify factors associated with ILD and the progression of ILD. Results: the study population comprised 70 patients: 35 patients with RA-ILD (cases) and 35 RA patients without ILD (controls). A greater percentage of cases had higher DAS28-ESR (p = 0.032) and HAQ values (p = 0.003). The variables associated with RA-ILD in the Cox regression analysis were disease activity (DAS28) (HR [95% CI], 2.47 [1.17–5.22]; p = 0.017) and high levels of ACPA (HR [95% CI], 2.90 [1.24–6.78]; p = 0.014), IL-18 in pg/mL (HR [95% CI], 1.06 [1.00–1.12]; p = 0.044), MCP-1/CCL2 in pg/mL (HR [95% CI], 1.03 [1.00–1.06]; p = 0.049), and SDF-1 in pg/mL (HR [95% CI], 1.00 [1.00–1.00]; p = 0.010). The only variable associated with the progression of ILD was IL-18 in pg/mL (HR [95% CI], 1.25 [1.07–1.46]; p = 0.004). Conclusion: inflammatory activity was higher in patients with RA-ILD than RA patients without ILD. Some cytokines were associated with both diagnosis and poorer prognosis in patients with RA-ILD.

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

Cited by 6 publications

References 51 publications

Impaired Regulation by IL-35 in Systemic Sclerosis

Impaired Regulation by IL-35 in Systemic Sclerosis

Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers

Inflammatory Biomarkers in the Diagnosis and Prognosis of Rheumatoid Arthritis–Associated Interstitial Lung Disease

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