The immunoregulatory role of IL‐35 in patients with interstitial lung disease. Issue 4 (17th November 2022)

• Record Type: Journal Article
• Authors: Osuna‐Gómez, Rubén; Barril, Silvia; Mulet, Maria; Zamora Atenza, Carlos; Millan‐Billi, Paloma; Pardessus, Ana; Brough, Douglas E.; Sabzevari, Helen; Semnani, Roshanak T.; Castillo, Diego; Vidal, Silvia
• Is Part Of: Immunology. Volume 168:Issue 4(2023)
• Page Start: 610
• Page End: 621
• Publication Date: 2022-11-17
• Subjects: CD4+ T cell -- fibrosis -- IL‐35; Immunology -- Periodicals
• DOI: 10.1111/imm.13596
• Languages: English
• ISSNs: 0019-2805

Abstract

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. Abstract : In the lung microenvironment of fibrotic patients, the concentration of IL‐35 is lower and the concentration of TGF‐β is higher than in non‐fibrotic patients. A higher TGF‐β: IL‐35 ratio in fibrotic patients is associated with an enhanced IL‐17 production and a reduced IL‐35 production by CD4+ T cells. The consequence of high TGF‐β: IL‐35 ratio is the induction of direct or indirect mechanisms to modulate immune cells in microenvironment (created with BioRender.com ).