Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects.
Y-box protein-1 (YB-1) is a known negative regulator of collagen (Col) expression by two different mechanisms, acting directly through binding to an interferon-gamma response element within the col1A2 promoter and/or by physically interacting with p300/Smad3, thereby abrogating the stimulatory effect of transforming growth factor-beta (TGF-beta). Here, we report that YB-1 activation via the Jak1 signaling pathway is required and sufficient to confer interferon-gamma-dependent activation of the smad7 gene. By binding to a bona fide recognition site within the smad7 promoter, YB-1 up-regulates smad7 transcription, which was additively enhanced by autoinhibitory TGF-beta signaling. Importantly, the anti-TGF-beta effect was not only supplied by induced Smad7 expression but was recapitulated in the context of the col1A2 promoter, where YB-1 overexpression abolished the trans-stimulatory TGF-beta effect in a dominant fashion. In conclusion, YB-1 is the main target of interferon-gamma signaling via Jak1 that exerts antifibrotic action by both interference with TGF-beta signaling and direct down-regulation of collagen expression.
Dooley
Steven
S
Institute of Clinical Chemistry and Pathobiochemistry, University Hospital Aachen, RWTH-Aachen, Germany. steven.dooley@med.ma.uni-heidelberg.de
Said
Harun M
HM
Gressner
Axel M
AM
Floege
Jürgen
J
En-Nia
Abdelaziz
A
Mertens
Peter R
PR
D000818:Animals; D002252:Carbon Tetrachloride Poisoning; D002460:Cell Line; D003094:Collagen / Q000235:genetics; D005355:Fibrosis / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000009:adverse effects* / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control; D051381:Rats; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D051906:Smad7 Protein; C497808:Smad7 protein, rat; D016212:Transforming Growth Factor beta; D051840:Y-Box-Binding Protein 1; D007371:Interferon-gamma; D003094:Collagen