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The immunoregulatory role of IL-35 in patients with interstitial lung disease |
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| Authors: | Rubén Osuna-Gómez Silvia Barril Maria Mulet Carlos Zamora Atenza Paloma Millan-Billi Ana Pardessus Douglas E. Brough Helen Sabzevari Roshanak T. Semnani Diego Castillo Silvia Vidal |
| Affiliation: | 1. Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain;2. Respiratory Department, Institut de Recerca Biomèdica de Lleida (IRBLleida), Hospital Universitari Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, Universitat de Lleida (UdL), Lleida, Spain Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;3. Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Respiratory Department, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain;4. Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;5. Precigen, Inc., Germantown, Maryland, USA;6. Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain Respiratory Department, Institut de Recerca Biomèdica de Lleida (IRBLleida), Hospital Universitari Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, Universitat de Lleida (UdL), Lleida, Spain Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain |
| Abstract: | 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. |
| Keywords: | CD4+ T cell fibrosis IL-35 |