Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 316; no. 3; pp. L487 - L497
• Main Authors: Zhang, Jie, Wang, Dan, Wang, Lei, Wang, Shaohua, Roden, Anja C., Zhao, Hao, Li, Xiujuan, Prakash, Y. S., Matteson, Eric L., Tschumperlin, Daniel J., Vassallo, Robert
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2019
• Subjects: Animal models; Arthritis; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Autoimmune diseases; Autoimmune Diseases - drug therapy; Biopsy; Cell proliferation; Extracellular matrix; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosis; Human behavior; Humans; Idiopathic Pulmonary Fibrosis - drug therapy; Idiopathic Pulmonary Fibrosis - pathology; Inhibitors; Interleukin-17 - pharmacology; Interleukins; Janus kinase; Kinases; Lung - pathology; Lung diseases; Lung Diseases, Interstitial - drug therapy; Lung Diseases, Interstitial - pathology; NF-κB protein; Pathogenesis; Patients; Pharmacology; Proteins; Pulmonary fibrosis; Receptors, Interleukin-17 - drug effects; Receptors, Interleukin-17 - metabolism; Rheumatoid arthritis; Ribonucleic acid; RNA; RNA-mediated interference; siRNA; NF-κB; IL-17A; RA-ILD; IL-17RA; STAT3; human lung fibroblast; rheumatoid arthritis; IPF; JAK inhibitors
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00301.2018

Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480—but not a JAK1/JAK3 selective inhibitor, tofacitinib—also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.