Suppression of FoxO6 by lipopolysaccharide in aged rat liver.
The beneficial role of FoxO during aging has been proposed for its promotion of resistance to oxidative stress and inhibition of pro-inflammatory mediators. On the other hand, NF-κB is a pro-inflammatory transcription factor which is a key mediator of inflammatory cytokine generation. However, the correlation between FoxO6 and NF-κB during aging has not fully been explored.The main purpose of the present study was to elucidate mechanisms underlying the protective role of FoxO6 in the maintenance of cellular homeostasis under potent pro-inflammatory conditions induced by LPS. Initial experimentation revealed that reduced FoxO6 activity during aging was caused by its phosphorylation, which suppressed its transcriptional activity in aged livers. Transfection with FoxO6-wt virus and FoxO6-siRNA in HepG2 cells revealed that FoxO6 phosphorylation by LPS leads to NF-κB activation via Akt and Pak1 pathways. Furthermore, Pak1 activity was increased in a phosphatidylinositol 3-kinase independent manner, and LPS-induced FoxO6 phosphorylation and FoxO6 inactivation were Pak1-dependent in nuclear fractions of cells. Further revealed Pak1 phosphorylation by LPS permitted interaction between FoxO6 and Akt.Current study suggests FoxO6 phosphorylation facilitates the nuclear translocation of NF-κB via Akt and Pak1 pathways induced by LPS in aged rats.
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Dae Hyun
DH
Kim
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Min Hi
MH
Park
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Ki Wung
KW
Chung
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Min Jo
MJ
Kim
In silico Toxicology Research Center, Korea Institute of Toxicology, Daejeon, Korea.
Daeui
D
Park
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Bonggi
B
Lee
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Eun Kyeong
EK
Lee
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Yeon Ja
YJ
Choi
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Nam Deuk
ND
Kim
Department of Physiology, The University of Texas Health Science Center at San Antonio, TX, USA.
Byung Pal
BP
Yu
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Hae Young
HY
Chung
D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D024202:Electrophoretic Mobility Shift Assay; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D054462:p21-Activated Kinases / Q000378:metabolism
D051858:Forkhead Transcription Factors; C562177:Foxo6 protein, rat; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; C515906:Pak1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases
Akt; FoxO6; Gerotarget; NF-κB; Pak1 pathway; aging