Signaling Molecule IL-19 Tied to IPF Progression, May Be Therapy Target

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Abnormally high levels of the signaling molecule interleukin 19 (IL-19) were detected in lung tissues from both mice and humans with idiopathic pulmonary fibrosis (IPF) in a recent study.

These findings indicate that IL-19 promotes IPF progression by activating the transforming growth factor-beta pathway, a key mediator of tissue scarring, or fibrosis. According to researchers, the results suggest that the IL-19 signaling molecule might be a new target for IPF treatments.

“Our study firstly highlights the deleterious [damaging] role of IL-19 on development of pulmonary fibrosis … and reinforces its promise as a new therapeutic target for intervention,” the team wrote.

The study, “Interleukin-19 Aggravates Pulmonary Fibrosis via Activating Fibroblast through TGF-β/Smad Pathway,” was published in the journal Mediators of Inflammation.

IPF is a chronic lung disease characterized by progressive lung scarring, leading to lung function decline. While the mechanisms underlying IPF are still elusive, it is known that a panoply of factors play a role.

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IL-19 is a small signaling protein previously shown to promote inflammation and damage to lung epithelial cells, which line the surface of the airways. Previous studies have linked its activity to other diseases, including inflammatory bowel disease, rheumatoid arthritis, and breast cancer.

While these findings support the potential of IL-19 as therapeutic target, its role in lung scarring diseases like IPF remains unknown.

To learn more, researchers at The First Affiliated Hospital of Nanjing Medical University, in China, analyzed gene expression (activity) data from tissues of IPF patients, as well as disease mouse models.

Analyses revealed the RNA levels of IL-19 were increased in fibrotic lesions compared with healthy lung tissues in both mice and human patients. Of note, RNA is the molecule that serves as a template for the production of proteins.

The team then evaluated the levels of IL-19 in the lungs of a standard IPF mouse model, in which animals are exposed to bleomycin to induce lung fibrosis. Again, they confirmed the presence of higher levels of the IL-19 protein in the animals’ lungs, as well as alpha-smooth muscle actin (alpha-SMA) — a marker of activated fibroblasts, which are connective tissue cells that contribute to fibrosis.

IL-19 also was found at high levels in the blood of bleomycin-treated mice.

Because interleukins can have either anti- or pro-fibrotic effects, researchers assessed the role of IL-19 in a human embryo lung fibroblast cell line, as well as in primary mouse lung fibroblasts. Specifically, they measured cells’ proliferation when exposed to increasing concentrations of the signaling molecule.

The cells proliferated, or grew more after being incubated with IL-19 (100 ng/mL) for 72 hours. IL-19 also enhanced their invasiveness — the ability to migrate and invade other tissues — and suppressed programmed cell death, known as apoptosis. Apoptosis is a protective quality control mechanism.

It also induced the expression or activity of fibrosis markers, like alpha-SMA and collagen 1. Both markers showed the highest increase when cells were exposed to both IL-19 and transforming growth factor-beta1 (TGF-beta1), a pro-fibrotic signaling protein.

Researchers conducted a computational analysis to further understand which pathways are linked to IL-19. This analysis revealed that IL-19 was associated with the activation of the TGF-beta/Smad signaling pathway. This later was confirmed in subsequent experiments in which researchers exposed fibroblasts to increasing concentrations of IL-19.

Using a chemical inhibitor of the TGF-beta/Smad signaling pathway, called LY2109761, they confirmed these results. Cells exposed to IL-19 together with the inhibitor no longer showed an increase in TGF-beta1 or in phosphorylated Smad2 and Smad3, two proteins associated with TGF-beta activation.

Also, LY2109761 significantly inhibited the fibroblasts’ enhanced proliferation and invasiveness driven by exposure to IL-19. The inhibitor also prevented fibroblasts from transforming into myofibroblasts — the cells responsible for the production and buildup of scar tissue.

Finally, researchers demonstrated the administration of IL-19 alone directly into the trachea of mice triggered lung fibrosis, as shown by an increase of fibrosis markers like alpha-SMA. Treatment with IL-19 also worsened lung scarring in mice previously exposed to bleomycin.

Overall, these results highlight the role of IL-19 in IPF development “by modulating fibroblasts through TGF-β/Smad pathway,” the team wrote, adding that the findings also show the signaling molecule’s promise as a therapeutic target.

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