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

Jie Zhang, Dan Wang, Lei Wang, Shaohua Wang, Anja Roden, Hao Zhao, Xiujuan Li, Y.s. Prakash, Eric Lawrence Matteson, Daniel J Tschumperlin, Robert Vassallo

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4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)L487-L497
JournalAmerican journal of physiology. Lung cellular and molecular physiology
Volume316
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Idiopathic Pulmonary Fibrosis
Interleukin-17
Interleukins
Interstitial Lung Diseases
Lung Diseases
Rheumatoid Arthritis
Fibroblasts
Lung
Fibrosis
Small Interfering RNA
Interleukin Receptors
Janus Kinase 2
Biopsy
Myofibroblasts
Pulmonary Fibrosis
Extracellular Matrix Proteins
RNA Interference
Autoimmune Diseases
Extracellular Matrix
Cell Proliferation

Keywords

  • human lung fibroblast
  • IL-17A
  • IL-17RA
  • IPF
  • JAK inhibitors
  • NF-κB
  • RA-ILD
  • rheumatoid arthritis
  • STAT3

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

@article{1fe58f482b724a3f9445fe44e954882c,
title = "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",
abstract = "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.",
keywords = "human lung fibroblast, IL-17A, IL-17RA, IPF, JAK inhibitors, NF-κB, RA-ILD, rheumatoid arthritis, STAT3",
author = "Jie Zhang and Dan Wang and Lei Wang and Shaohua Wang and Anja Roden and Hao Zhao and Xiujuan Li and Y.s. Prakash and Matteson, {Eric Lawrence} and Tschumperlin, {Daniel J} and Robert Vassallo",
year = "2019",
month = "3",
day = "1",
doi = "10.1152/ajplung.00301.2018",
language = "English (US)",
volume = "316",
pages = "L487--L497",
journal = "American Journal of Physiology - Lung Cellular and Molecular Physiology",
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T1 - 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

AU - Zhang, Jie

AU - Wang, Dan

AU - Wang, Lei

AU - Wang, Shaohua

AU - Roden, Anja

AU - Zhao, Hao

AU - Li, Xiujuan

AU - Prakash, Y.s.

AU - Matteson, Eric Lawrence

AU - Tschumperlin, Daniel J

AU - Vassallo, Robert

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - human lung fibroblast

KW - IL-17A

KW - IL-17RA

KW - IPF

KW - JAK inhibitors

KW - NF-κB

KW - RA-ILD

KW - rheumatoid arthritis

KW - STAT3

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U2 - 10.1152/ajplung.00301.2018

DO - 10.1152/ajplung.00301.2018

M3 - Article

VL - 316

SP - L487-L497

JO - American Journal of Physiology - Lung Cellular and Molecular Physiology

JF - American Journal of Physiology - Lung Cellular and Molecular Physiology

SN - 1040-0605

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