IL-35 subunit EBI3 alleviates bleomycin-induced pulmonary fibrosis via suppressing DNA enrichment of STAT3

Donghong Chen; Guofeng Zheng; Qing Yang; Le Luo; Jinglian Shen

doi:10.1186/s12931-021-01858-x

IL-35 subunit EBI3 alleviates bleomycin-induced pulmonary fibrosis via suppressing DNA enrichment of STAT3

Respir Res. 2021 Oct 28;22(1):280. doi: 10.1186/s12931-021-01858-x.

Authors

Donghong Chen^#¹, Guofeng Zheng^#¹, Qing Yang², Le Luo³, Jinglian Shen⁴

Affiliations

¹ Department of Respiratory Medicine, The Fourth Affiliated Hospital of China Medical University/China Medical University, Seven South Road, Shenyang, 110005, Liaoning, China.
² Emergency Department, The Fourth Affiliated Hospital of China Medical University/China Medical University, Seven South Road, Shenyang, 110005, Liaoning, China.
³ Shanghai Yunhao Biotech Center, Shanghai, 200000, China.
⁴ Emergency Department, The Fourth Affiliated Hospital of China Medical University/China Medical University, Seven South Road, Shenyang, 110005, Liaoning, China. jlshen@cmu.edu.cn.

^# Contributed equally.

Abstract

Background: IL-35 subunit EBI3 is up-regulated in pulmonary fibrosis tissues. In this study, we investigated the pathological role of EBI3 in pulmonary fibrosis and dissected the underlying molecular mechanism.

Methods: Bleomycin-induced pulmonary fibrosis mouse model was established, and samples were performed gene expression analyses through RNAseq, qRT-PCR and Western blot. Wild type and EBI3 knockout mice were exposed to bleomycin to investigate the pathological role of IL-35, via lung function and gene expression analyses. Primary lung epithelial cells were used to dissect the regulatory mechanism of EBI3 on STAT1/STAT4 and STAT3.

Results: IL-35 was elevated in both human and mouse with pulmonary fibrosis. EBI3 knockdown aggravated the symptoms of pulmonary fibrosis in mice. EBI3 deficiency enhanced the expressions of fibrotic and extracellular matrix-associated genes. Mechanistically, IL-35 activated STAT1 and STAT4, which in turn suppressed DNA enrichment of STAT3 and inhibited the fibrosis process.

Conclusion: IL-35 might be one of the potential therapeutic targets for bleomycin-induced pulmonary fibrosis.

Keywords: DNA enrichment; IL-35; Pulmonary fibrosis; STAT1/STAT4; STAT3.

MeSH terms

Adult
Animals
Binding Sites
Bleomycin
Case-Control Studies
Cells, Cultured
Disease Models, Animal
Epithelial Cells / drug effects
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Extracellular Matrix Proteins / genetics
Extracellular Matrix Proteins / metabolism
Female
Gene Expression Regulation
Humans
Interleukin-6 / pharmacology
Interleukins / genetics
Interleukins / metabolism
Interleukins / pharmacology
Lung / drug effects
Lung / metabolism*
Lung / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / metabolism*
Phosphorylation
Pulmonary Fibrosis / chemically induced
Pulmonary Fibrosis / metabolism*
Pulmonary Fibrosis / pathology
Receptors, Cytokine / genetics
Receptors, Cytokine / metabolism*
STAT1 Transcription Factor / metabolism
STAT3 Transcription Factor / metabolism*
STAT4 Transcription Factor / metabolism
Young Adult

Substances

EBI3 protein, human
Ebi3 protein, mouse
Extracellular Matrix Proteins
IL6 protein, human
Interleukin-6
Interleukins
Minor Histocompatibility Antigens
Receptors, Cytokine
STAT1 Transcription Factor
STAT3 Transcription Factor
STAT4 Transcription Factor
Stat1 protein, mouse
Stat3 protein, mouse
Stat4 protein, mouse
interleukin-35, human
Bleomycin