TY - JOUR
T1 - Activation of retinoic X receptor and peroxisome proliferator-activated receptor-γ inhibits nitric oxide and tumor necrosis factor-α production in rat Kupffer cells
AU - Uchimura, Koutaro
AU - Nakamuta, Makoto
AU - Enjoji, Munechika
AU - Irie, Takashi
AU - Sugimoto, Rie
AU - Muta, Tatsushi
AU - Iwamoto, Hiroaki
AU - Nawata, Hajime
N1 - Funding Information:
Supported by a Grant-in-Aid (10670485, 12670498, 12670497) for Scientific Research from the Ministry of Education, Science and Culture, Japan, and by a grant from Mitsui Life Insurance Public Welfare Enterprise, Japan.
PY - 2001/1
Y1 - 2001/1
N2 - Activators of peroxisome proliferator-activated receptor γ (PPARγ), which forms a heterodimer with retinoic X receptor (RXR), inhibit the production of certain inflammatory mediators. To clarify the role of the PPARγ:RXR signaling pathway in Kupffer cells, we studied the effect of an RXR agonist and PPARγ agonist on LPS-induced nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production. An RXR-specific agonist, Ro47-5944, and a PPARγ-specific agonist, AD4833 (pioglitazone hydrochloride), each inhibited LPS-induced NO and TNF-α production. The combined treatment of Ro47-5944 and AD4833 resulted in enhanced inhibition, and suppressed the mRNA levels of NO and TNF-α. PPARγ:RXR activation did not affect the level of LPS-induced phosphorylation of c-jun N-terminal kinase and p38 mitogen-activated protein kinase. PPARγ:RXR activation also did not affect nuclear factor kappa B (NF-κB) nuclear translocation nor NF-κB and activator protein 1 (AP-1) activation in the electrophoretic mobility-shift assay. Finally, PPARγ:RXR activation suppressed the LPS-induced promoter activity of the NF-κB-luciferase reporter gene in RAW 264.7 cells. These data imply that PPARγ:RXR activation suppresses LPS-induced NO and TNF-α production in Kupffer cells, and that this inhibition occurred at the transcriptional level. Although no consensus PPARγ:RXR-responsive element in the promoter regions of the inducible isoform of nitric oxide synthase (iNOS) and TNF-α genes was found, PPARγ:RXR may interfere with NF-κB and AP-1 transcriptional activity. Our data also suggest a potential therapeutic approach for moderating hepatic injury such as endotoxin shock in which Kupffer cell activation has been implicated.
AB - Activators of peroxisome proliferator-activated receptor γ (PPARγ), which forms a heterodimer with retinoic X receptor (RXR), inhibit the production of certain inflammatory mediators. To clarify the role of the PPARγ:RXR signaling pathway in Kupffer cells, we studied the effect of an RXR agonist and PPARγ agonist on LPS-induced nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production. An RXR-specific agonist, Ro47-5944, and a PPARγ-specific agonist, AD4833 (pioglitazone hydrochloride), each inhibited LPS-induced NO and TNF-α production. The combined treatment of Ro47-5944 and AD4833 resulted in enhanced inhibition, and suppressed the mRNA levels of NO and TNF-α. PPARγ:RXR activation did not affect the level of LPS-induced phosphorylation of c-jun N-terminal kinase and p38 mitogen-activated protein kinase. PPARγ:RXR activation also did not affect nuclear factor kappa B (NF-κB) nuclear translocation nor NF-κB and activator protein 1 (AP-1) activation in the electrophoretic mobility-shift assay. Finally, PPARγ:RXR activation suppressed the LPS-induced promoter activity of the NF-κB-luciferase reporter gene in RAW 264.7 cells. These data imply that PPARγ:RXR activation suppresses LPS-induced NO and TNF-α production in Kupffer cells, and that this inhibition occurred at the transcriptional level. Although no consensus PPARγ:RXR-responsive element in the promoter regions of the inducible isoform of nitric oxide synthase (iNOS) and TNF-α genes was found, PPARγ:RXR may interfere with NF-κB and AP-1 transcriptional activity. Our data also suggest a potential therapeutic approach for moderating hepatic injury such as endotoxin shock in which Kupffer cell activation has been implicated.
UR - http://www.scopus.com/inward/record.url?scp=0035200209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035200209&partnerID=8YFLogxK
U2 - 10.1053/jhep.2001.21145
DO - 10.1053/jhep.2001.21145
M3 - Article
C2 - 11124825
AN - SCOPUS:0035200209
VL - 33
SP - 91
EP - 99
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 1
ER -