Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy.
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is characterised by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. Sphingosine-1-phosphate (S1P) signalling plays a critical role in pulmonary fibrosis.


METHODS
S1P lyase (S1PL) expression in peripheral blood mononuclear cells (PBMCs) was correlated with pulmonary functions and overall survival; used a murine model to check the role of S1PL on the fibrogenesis and a cell culture system to study the effect of S1PL expression on transforming growth factor (TGF)-β- and S1P-induced fibroblast differentiation.


RESULTS
S1PL expression was upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. TGF-β increased the expression of S1PL in human lung fibroblasts via activation and binding of Smad3 transcription factor to Sgpl1 promoter. Overexpression of S1PL attenuated TGF-β-induced and S1P-induced differentiation of human lung fibroblasts through regulation of the expression of LC3 and beclin 1. Knockdown of S1PL (Sgpl1(+/-)) in mice augmented bleomycin-induced pulmonary fibrosis, and patients with IPF reduced Sgpl1 mRNA expression in PBMCs exhibited higher severity of fibrosis and lower survival rate.


CONCLUSIONS
These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.
Department of Pharmacology, The University of Illinois, Chicago, Illinois, USA.
Long Shuang
LS
Huang
Department of Medicine,The University of Illinois, Chicago, Illinois, USA.
Evgeny V
EV
Berdyshev
Department of Biology, The University of Illinois, Chicago, Illinois, USA.
John T
JT
Tran
Department of Urology, The University of Illinois, Chicago, Illinois, USA.
Lishi
L
Xie
Department of Medicine,The University of Illinois, Chicago, Illinois, USA.
Jiwang
J
Chen
Department of Biochemistry and Molecular Genetics, The University of Illinois, Chicago, Illinois, USA.
David L
DL
Ebenezer
Department of Medicine,The University of Illinois, Chicago, Illinois, USA.
Biji
B
Mathew
Department of Medicine,The University of Illinois, Chicago, Illinois, USA.
Irina
I
Gorshkova
Department of Pharmacology, The University of Illinois, Chicago, Illinois, USA Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Wei
W
Zhang
Department of Pediatrics, The University of Illinois, Chicago, Illinois, USA.
Sekhar P
SP
Reddy
Department of Pediatrics, The University of Illinois, Chicago, Illinois, USA.
Anantha
A
Harijith
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu, China.
Gang
G
Wang
Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
Carol
C
Feghali-Bostwick
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Imre
I
Noth
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Shwu-Fan
SF
Ma
Department of Medicine, University of Arizona, Tucson, Arizona, USA.
Tong
T
Zhou
Department of Medicine, University of Arizona, Tucson, Arizona, USA.
Wenli
W
Ma
Department of Medicine, University of Arizona, Tucson, Arizona, USA.
Joe G N
JG
Garcia
Department of Pharmacology, The University of Illinois, Chicago, Illinois, USA Department of Medicine,The University of Illinois, Chicago, Illinois, USA.
Viswanathan
V
Natarajan
D000446:Aldehyde-Lyases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)
Idiopathic pulmonary fibrosis