Rosiglitazone Regulates TLR4 and Rescues HO-1 and NRF2 Expression in Myometrial and Decidual Macrophages in Inflammation-Induced Preterm Birth.
Elevated inflammation accounts for approximately 30% of preterm birth (PTB) cases. We previously reported that targeting the peroxisome proliferator-activated receptor gamma (PPARγ) pathway reduced the incidence of PTB in the mouse model of endotoxin-induced PTB. The PPARγ has proven anti-inflammatory functions and its activation via rosiglitazone significantly downregulated the systemic inflammatory response and reduced PTB and stillbirth rate by 30% and 41%, respectively, in our model. Oxidative stress is inseparable from inflammation, and rosiglitazone has a reported antioxidative activity. In the current study, we therefore aimed to evaluate whether rosiglitazone treatment had effects outside of inflammatory pathway, specifically on the antioxidation pathway in our model.



Pregnant C57BL/6J mice (E16.5) were treated with phosphate-buffered saline (PBS), rosiglitazone (Rosi), lipopolysaccharide (LPS; 10µg in 200µL 1XPBS), or LPS + Rosi (6 hours after the LPS injection). The myometrial and decidual tissues were collected and processed for macrophage isolation using magnetic cell sorting and F4/80+ antibody. Expression levels of antioxidative factors- Nrf2 and Ho-1-along with the LPS receptor Tlr4 were quantified by quantitative polymerase chain reaction. The protein levels were assessed by immunofluorescence staining.



Both the decidual and myometrial macrophages from the LPS-treated animals showed significantly lowered expression of Ho-1 and Nrf2 and higher expression of Tlr4 when compared to the PBS control group. The macrophages from the animals in the LPS + Rosi group had significantly elevated expression of Ho-1 and Nrf2 and downregulated expression of Tlr4 when compared to the LPS group.



Rosiglitazone administration prevents PTB by downregulating inflammation and upregulating antioxidative response.
1 Department of Physiology, School of Medicine, Wayne State University, Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI, USA.
Leena
L
Kadam
2 Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI, USA.|3 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Services, Detroit, MI, USA.|4 Department of Immunology and Microbiology, School of Medicine, Wayne State University, Detroit, MI, USA.
Nardhy
N
Gomez-Lopez
2 Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI, USA.|3 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Services, Detroit, MI, USA.
Tara N
TN
Mial
2 Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI, USA.
Hamid-Reza
HR
Kohan-Ghadr
2 Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI, USA.
Sascha
S
Drewlo
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D003656:Decidua / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009215:Myometrium / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D047928:Premature Birth / Q000139:chemically induced / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D000975:Antioxidants; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D045162:Thiazolidinediones; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000077154:Rosiglitazone; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
LPS; PPARγ; antioxidant; macrophages; preterm birth