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15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide (LPS)-induced acute liver injury.

Abstract The NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of prostaglandin E2 (PGE2), converting the pro-inflammatory PGE2 to the anti-inflammatory 15-keto-PGE2 (an endogenous ligand for peroxisome proliferator-activated receptor-gamma [PPAR-γ]). To evaluate the significance of 15-PGDH/15-keto-PGE2 cascade in liver inflammation and tissue injury, we generated transgenic mice with targeted expression of 15-PGDH in the liver (15-PGDH Tg) and the animals were subjected to lipopolysaccharide (LPS)/Galactosamine (GalN)-induced acute liver inflammation and injury. Compared to the wild type mice, the 15-PGDH Tg mice showed lower levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), less liver tissue damage, less hepatic apoptosis/necrosis, less macrophage activation, and lower inflammatory cytokine production. In cultured Kupffer cells, treatment with 15-keto-PGE2 or the conditioned medium (CM) from 15-PGDH Tg hepatocyes inhibited LPS-induced cytokine production, in vitro. Both 15-keto-PGE2 and the CM from15-PGDH Tg hepatocyes also up-regulated the expression of PPAR-γ downstream genes in Kupffer cells. In cultured hepatocytes, 15-keto-PGE2 treatment or 15-PGDH overexpression did not influence TNF-α-induced hepatocyte apoptosis. These findings suggest that 15-PGDH protects against LPS/GalN-induced liver injury and the effect is mediated via 15-keto-PGE2, which activates PPAR-γ in Kupffer cells and thus inhibits their ability to produce inflammatory cytokines. Accordingly, we observed that the PPAR-γ antagonist, GW9662, reversed the effect of 15-keto-PGE2 in Kupffer cell in vitro and restored the susceptibility of 15-PGDH Tg mice to LPS/GalN-induced acute liver injury in vivo. Collectively, our findings suggest that 15-PGDH-derived 15-keto-PGE2 from hepatocytes is able to activate PPAR-γ and inhibit inflammatory cytokine production in Kupffer cells and that this paracrine mechanism negatively regulates LPS-induced necro-inflammatory response in the liver. Therefore, induction of 15-PGDH expression or utilization of 15-keto-PGE2 analogue may have therapeutic benefits for the treatment of endotoxin-associated liver inflammation/injury.
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PMID- 28423012
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170419
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - 15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide
      (LPS)-induced acute liver injury.
PG  - e0176106
LID - 10.1371/journal.pone.0176106 [doi]
AB  - The NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the 
      oxidation of the 15(S)-hydroxyl group of prostaglandin E2 (PGE2), converting the 
      pro-inflammatory PGE2 to the anti-inflammatory 15-keto-PGE2 (an endogenous ligand
      for peroxisome proliferator-activated receptor-gamma [PPAR-gamma]). To evaluate
      the significance of 15-PGDH/15-keto-PGE2 cascade in liver inflammation and tissue
      injury, we generated transgenic mice with targeted expression of 15-PGDH in the
      liver (15-PGDH Tg) and the animals were subjected to lipopolysaccharide
      (LPS)/Galactosamine (GalN)-induced acute liver inflammation and injury. Compared 
      to the wild type mice, the 15-PGDH Tg mice showed lower levels of alanine
      aminotransferase (ALT) and aspartate aminotransferase (AST), less liver tissue
      damage, less hepatic apoptosis/necrosis, less macrophage activation, and lower
      inflammatory cytokine production. In cultured Kupffer cells, treatment with
      15-keto-PGE2 or the conditioned medium (CM) from 15-PGDH Tg hepatocyes inhibited 
      LPS-induced cytokine production, in vitro. Both 15-keto-PGE2 and the CM
      from15-PGDH Tg hepatocyes also up-regulated the expression of PPAR-gamma
      downstream genes in Kupffer cells. In cultured hepatocytes, 15-keto-PGE2
      treatment or 15-PGDH overexpression did not influence TNF-alpha-induced
      hepatocyte apoptosis. These findings suggest that 15-PGDH protects against
      LPS/GalN-induced liver injury and the effect is mediated via 15-keto-PGE2, which 
      activates PPAR-gamma in Kupffer cells and thus inhibits their ability to produce 
      inflammatory cytokines. Accordingly, we observed that the PPAR-gamma antagonist, 
      GW9662, reversed the effect of 15-keto-PGE2 in Kupffer cell in vitro and restored
      the susceptibility of 15-PGDH Tg mice to LPS/GalN-induced acute liver injury in
      vivo. Collectively, our findings suggest that 15-PGDH-derived 15-keto-PGE2 from
      hepatocytes is able to activate PPAR-gamma and inhibit inflammatory cytokine
      production in Kupffer cells and that this paracrine mechanism negatively
      regulates LPS-induced necro-inflammatory response in the liver. Therefore,
      induction of 15-PGDH expression or utilization of 15-keto-PGE2 analogue may have 
      therapeutic benefits for the treatment of endotoxin-associated liver
      inflammation/injury.
FAU - Yao, Lu
AU  - Yao L
AD  - Department of Pathology and Laboratory Medicine, Tulane University School of
      Medicine, New Orleans, LA, United States of America.
FAU - Chen, Weina
AU  - Chen W
AD  - Department of Pathology and Laboratory Medicine, Tulane University School of
      Medicine, New Orleans, LA, United States of America.
FAU - Song, Kyoungsub
AU  - Song K
AD  - Department of Pathology and Laboratory Medicine, Tulane University School of
      Medicine, New Orleans, LA, United States of America.
FAU - Han, Chang
AU  - Han C
AD  - Department of Pathology and Laboratory Medicine, Tulane University School of
      Medicine, New Orleans, LA, United States of America.
FAU - Gandhi, Chandrashekhar R
AU  - Gandhi CR
AD  - Department of Pediatrics, Cincinnati Children's Hospital Medical Center and
      Department of Surgery, University of Cincinnati, Cincinnati, United States of
      America.
FAU - Lim, Kyu
AU  - Lim K
AD  - Department of Biochemistry, College of Medicine, Cancer Research Institute and
      Infection Signaling Network Research Center, Chungnam National University,
      Daejeon, Korea.
FAU - Wu, Tong
AU  - Wu T
AD  - Department of Pathology and Laboratory Medicine, Tulane University School of
      Medicine, New Orleans, LA, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20170419
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2016/10/11 [received]
PHST- 2017/04/05 [accepted]
AID - 10.1371/journal.pone.0176106 [doi]
AID - PONE-D-16-39778 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 19;12(4):e0176106. doi: 10.1371/journal.pone.0176106.
      eCollection 2017.

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