Y-box Protein-1 Is the Crucial Mediator of Antifibrotic Interferon-γ Effects

Steven Dooley,Harun M Said,Axel M Gressner,Jürgen Floege,Abdelaziz En-Nia,Peter R Mertens

doi:10.1074/jbc.m510215200

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-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.

Highlights

Deposition, Y-box protein-1 (YB-1) was identified as a negative regulator in glomerular mesangial cells, where it trans-activates transcription of the matrix metalloproteinase-2 gene via combinatorial interactions with p53 and AP-2, which may be antagonized by nonmetastasizing protein 23 (Nm23) [9]
The role of TGF-␤ as the principal factor inducing collagen expression and leading to tissue fibrosis has been suggested by studies showing increased TGF-␤ and col1 gene expression occurring in parallel [12, 13]
Clinical data suggest that IFN-␥ induces the expression of Smad7, which prevents endogenous TGF-␤ from down-regulating the ongoing tissue-damaging Th1 response [40]

Summary

Introduction

Deposition, YB-1 was identified as a negative regulator in glomerular mesangial cells, where it trans-activates transcription of the matrix metalloproteinase-2 gene via combinatorial interactions with p53 and AP-2, which may be antagonized by nonmetastasizing protein 23 (Nm23) [9]. A functional Y-box element was identified within the proximal col1A1 gene promoter (collagen Y-box element), which is conserved between humans, rats, and mice [11]. These results indicate that YB-1 is a key regulator of ECM components involved in scarring processes and that YB-1 itself is activated by an IFN-␥-dependent signaling pathway. More detailed studies with primary cultures of in vitro activated HSC and an activated HSC clone derived from cirrhotic rat liver, CFSC-2G, have delineated a TGF-␤-dependent pathway leading to col1A2 gene transcription and revealed a cooperation between transcription factors Sp1 and Smad3/4 [16]. We addressed the question of whether YB-1 confers the IFN-␥-inhibitory effect on TGF-␤ activity by up-regulating smad gene expression

Methods

Results

Conclusion