Y-box protein-1 is the crucial mediator of antifibrotic interferon-γ effects

Abstract

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-γ response element within the col1A2 promoter and/or by physically interacting with p300/Smad3, thereby abrogating the stimulatory effect of transforming growth factor-β(TGF-β). Here, we report that YB-1 activation via the Jak1 signaling pathway is required and sufficient to confer interferon-γ-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 auto-inhibitory TGF-β signaling. Importantly, the anti-TGF-β 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-β effect in a dominant fashion. In conclusion, YB-1 is the main target of interferon-γ signaling via Jak1 that exerts antifibrotic action by both interference with TGF-β signaling and direct down-regulation of collagen expression. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.