Tribbles homologue 3 stimulates canonical TGF-beta signalling to regulate fibroblast activation and tissue fibrosis

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F16%3A10325226" target="_blank" >RIV/00216208:11110/16:10325226 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1136/annrheumdis-2014-206234" target="_blank" >http://dx.doi.org/10.1136/annrheumdis-2014-206234</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1136/annrheumdis-2014-206234" target="_blank" >10.1136/annrheumdis-2014-206234</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Tribbles homologue 3 stimulates canonical TGF-beta signalling to regulate fibroblast activation and tissue fibrosis

Popis výsledku v původním jazyce

Objectives Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc). Methods The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3. Results TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-beta (TGF-beta)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-beta signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-beta and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-beta receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation. Conclusions The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-beta induces TRB3, which in turn activates canonical TGF-beta/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-beta signalling in SSc.

Název v anglickém jazyce

Tribbles homologue 3 stimulates canonical TGF-beta signalling to regulate fibroblast activation and tissue fibrosis

Popis výsledku anglicky

Objectives Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc). Methods The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3. Results TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-beta (TGF-beta)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-beta signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-beta and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-beta receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation. Conclusions The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-beta induces TRB3, which in turn activates canonical TGF-beta/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-beta signalling in SSc.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FE - Ostatní obory vnitřního lékařství

OECD FORD obor

—

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Annals of the Rheumatic Diseases

ISSN

0003-4967

e-ISSN

—

Svazek periodika

75

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

8

Strana od-do

609-616

Kód UT WoS článku

000371077700020

EID výsledku v databázi Scopus

2-s2.0-84960115459