Upregulation of FoxO 1 Signaling Mediates the Proinflammatory Cytokine Upregulation in the Macrophage from Polycystic Ovary Syndrome Patients.
BACKGROUND
Chronic activation of macrophage-mediated inflammatory signals in insulin-sensitive metabolic tissues is thought to be one of the causes of insulin resistance-one of the hallmarks of the metabolic syndrome. Insulin resistance is a feature of polycystic ovary syndrome (PCOS) and is related to mitochondrial and endothelial function.


METHODS
In the present study, we investigated the phosphorylation level of FoxO 1, which is suppressed by the action of AKT, triggers the TLR4 inflammatory signaling pathway in the macrophages, from polycystic ovary syndrome patients or normal subjects. Then we investigated the influence of phosphorylation level of FoxO 1FoxO 1 on the induction of proinflammatory cytokines in the macrophages and the influence by FoxO FoxO 1 knockdown on the insulin-induced glucose uptake in PCOS macrophages.


RESULTS
Our results demonstrated that the significantly high level of FoxO 1FoxO 1 phosphorylation correlated with the production of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α in the macrophages from PCOS patients. The high level of FoxO 1FoxO 1 phosphorylation enhanced the TLR-4 signaling in response to LPS, and the FoxO FoxO 1 knockdown inhibited the insulin-induced glucose uptake in PCOS macrophages.


CONCLUSIONS
The findings of this paper suggest an intriguing regulatory transcriptional/signaling loop in macrophages that may contribute to maintain and exacerbate inflammation and insulin resistance in PCOS macrophages.
Ning
N
Li
Xiaoyan
X
Wang
Xiaojie
X
Wang
Hongna
H
Yu
Li
L
Lin
Chengming
C
Sun
Peng
P
Liu
Yongli
Y
Chu
Jianqing
J
Hou
D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011085:Polycystic Ovary Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D055815:Young Adult
D016207:Cytokines; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D018836:Inflammation Mediators; D007328:Insulin; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose