The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib

Wenxia Wang, Swati Bhattacharyya*, Roberta Goncalves Marangoni, Mary Carns, Kathleen Dennis-Aren, Anjana V Yeldandi, Jun Wei, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized. Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.

Original languageEnglish (US)
JournalJournal of Scleroderma and Related Disorders
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Systemic Scleroderma
Fibrosis
Skin
Lung
Biopsy
Interleukin-6
Myofibroblasts
Bleomycin
tofacitinib
Computational Biology
Cues
Therapeutics
Animal Models
Phosphorylation
Morbidity
Food
Mortality
Pharmaceutical Preparations
Genes

Keywords

  • fibrosis
  • interleukin 6
  • JAK
  • STAT3
  • systemic sclerosis
  • Tofacitinib

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

@article{5c4a20e0693e46dda1e2ccc0c49ce904,
title = "The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib",
abstract = "Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized. Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.",
keywords = "fibrosis, interleukin 6, JAK, STAT3, systemic sclerosis, Tofacitinib",
author = "Wenxia Wang and Swati Bhattacharyya and {Goncalves Marangoni}, Roberta and Mary Carns and Kathleen Dennis-Aren and Yeldandi, {Anjana V} and Jun Wei and John Varga",
year = "2019",
month = "1",
day = "1",
doi = "10.1177/2397198319865367",
language = "English (US)",
journal = "Journal of Scleroderma and Related Disorders",
issn = "2397-1983",
publisher = "SAGE Publications Ltd",

}

The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib. / Wang, Wenxia; Bhattacharyya, Swati; Goncalves Marangoni, Roberta; Carns, Mary; Dennis-Aren, Kathleen; Yeldandi, Anjana V; Wei, Jun; Varga, John.

In: Journal of Scleroderma and Related Disorders, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib

AU - Wang, Wenxia

AU - Bhattacharyya, Swati

AU - Goncalves Marangoni, Roberta

AU - Carns, Mary

AU - Dennis-Aren, Kathleen

AU - Yeldandi, Anjana V

AU - Wei, Jun

AU - Varga, John

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized. Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.

AB - Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized. Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.

KW - fibrosis

KW - interleukin 6

KW - JAK

KW - STAT3

KW - systemic sclerosis

KW - Tofacitinib

UR - http://www.scopus.com/inward/record.url?scp=85071020071&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071020071&partnerID=8YFLogxK

U2 - 10.1177/2397198319865367

DO - 10.1177/2397198319865367

M3 - Article

JO - Journal of Scleroderma and Related Disorders

JF - Journal of Scleroderma and Related Disorders

SN - 2397-1983

ER -