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ID 118786
Title Alternative
リンパ球特異的タンパク質チロシンキナーゼ特異的阻害剤A-770041は、制御性T細胞におけるTGF-β産生の抑制を介して肺線維症の進行を抑制する。
Lck inhibition attenuate lung fibrosis by suppressing Treg activity
Author
Imakura, Takeshi Tokushima University
Murakami, Kojin Tokushima University
Yamashita, Yuya Tokushima University
Keywords
Idiopathic pulmonary fibrosis
Lymphocyte-specific protein tyrosine kinase
TGF-β
Regulatory T-cells
Content Type
Thesis or Dissertation
Description
Background
Lymphocyte-specific protein tyrosine kinase (Lck) is a member of the Src family of tyrosine kinases. The significance of Lck inhibition in lung fibrosis has not yet been fully elucidated, even though lung fibrosis is commonly preceded by inflammation caused by infiltration of Tcells expressing Lck. In this study, we examined the effect of Lck inhibition in an experimental mouse model of lung fibrosis. We also evaluated the effect of Lck inhibition on the expression of TGF-β1, an inhibitory cytokine regulating the immune function, in regulatory T-cells (Tregs).
Methods
Lung fibrosis was induced in mice by intratracheal administration of bleomycin. A-770041, a Lck-specific inhibitor, was administrated daily by gavage. Tregs were isolated from the lung using a CD4+CD25+ Regulatory T-cell Isolation Kit. The expression of Tgfb on Tregs was examined by flow cytometry and quantitative polymerase chain reaction. The concentration of TGF-β in bronchoalveolar lavage fluid (BALF) and cell culture supernatant from Tregs was quantified by an enzyme-linked immunosorbent assay.
Results
A-770041 inhibited the phosphorylation of Lck in murine lymphocytes to the same degree as nintedanib. A-770041 attenuated lung fibrosis in bleomycin-treated mice and reduced the concentration of TGF-β in BALF. A flow-cytometry analysis showed that A-770041 reduced the number of Tregs producing TGF-β1 in the lung. In isolated Tregs, Lck inhibition by A-770041 decreased the Tgfb mRNA level as well as the concentration of TGF-β in the supernatant.
Conclusions
These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-β production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis.
Journal Title
PLOS ONE
ISSN
19326203
Publisher
PLOS
Volume
17
Issue
10
Start Page
e0275987
Published Date
2022-10-27
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Kozo Kagawaの学位論文として提出され,学位審査・授与の対象となっている。
Rights
This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3764号
Diploma Number
甲医第1589号
Granted Date
2023-11-24
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital