Mitochondrial ROS Inhibit Unfolded Protein Response Induced by Inflammatory Mediators in Liver Cells.

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Duvigneau, Catharina; Müllebner, Andrea

Abstrakt

Inflammatory cytokines, when released in excess affect liver mitochondria (stimulating mitochondrial ROS (mROS), and inhibiting ATP synthesis) and compromise liver function (inducing acute phase reaction and impairing endoplasmic reticulum function). The objective of this study was to clarify the impact of mROS on hepatocyte dysfunction induced by inflammatory cytokines. Conditioned media (CM) containing diverse inflammatory cytokine pattern were generated by incubating rat white blood cells with lipopolysaccaride (LPS). Content of inflammatory cytokines was determined by multiplex assays. Rat hepatocytes were incubated with CM, examined by confocal microscopy (mitochondrial potential = Δψ and mitochondrial ROS = mROS), and analysed by RT-PCR for determination of gene expression (ER stress/unfolded protein response (UPR) (GRP78, XBP1, and spliced XBP1, an early upstream marker of UPR, as well as IL6, a major regulator of acute phase response). CM increased mROS, decreased Δψ, and upregulated expression of IL6 and UPR genes. Low contents of TNF-alpha in CM were coincident with upregulation of IL6 mRNA. Higher levels of TNFalpha were coincident additionally with upregulation of markers for ER-stress/UPR, but not with mROS levels. A mitochondriatargeted ROS scavenger, Mito-TEMPO significantly attenuated the levels of mROS and simultaneously decreased IL6 mRNA levels. In contrast, GRP78 and CHOP were upregulated in the presence of mito-TEMPO, while spliced XBP1 mRNA, was not affected. Our data show that mROS stimulate the production of IL6 and inhibit expression of UPR genes. Thus our data suggest that mROS may enhance hepatic dysfunction by slowing down recovery of ER stress.

ISSN/eISSN

0891-5849 -

WoS ID

WOS:000284348000377

Präsentationsart

Vortrag

Konferenzort

Orlando, FL