The activation of NF-kappaB through Akt-induced FOXO1 phosphorylation during aging and its modulation by calorie restriction.
Insulin-induced PI3K/Akt activation is known to inhibit a family of Forkhead transcription factors (FOXO), which can lead to increased oxidative stress in several model organisms. One of major transcription factors activated by oxidative stress and responsible for the production of many proinflammatory cytokines is NF-kappaB. In the present study, We were carried out to determine the relationship between FOXO1 and NF-kappaB activation using HEK293T cells and aged kidney isolated from ad libitum fed (AL) and 40% calorie restriction (CR) rats. Results showed that phosphorylation of FOXO1 and NF-kappaB activation were significantly increased in old rats. Moreover, FOXO1 phosphorylation and NF-kappaB activation were shown to be significantly lower in the CR rats compared with 24-month-old AL rats. To further explore the molecular link between FOXO and NF-kappaB, we performed transfection experiments with FOXO-mutant plasmid in cultured HEK293T cells. Treatment of the cell with insulin led to NF-kappaB activation through the phosphorylation of FOXO via the PI3K/Akt pathway. These results indicate that insulin promoted NF-kappaB activation through phosphorylation of FOXO1 by upregulating PI3K/Akt signaling. We conclude that the phosphorylation of FOXO1 regulates NF-kappaB nuclear translocation by activating PI3K/Akt during aging, which was suppressed by the hypoinsulinemic action of CR.
Kim
Dae Hyun
DH
Department of Pharmacy, College of Pharmacy, Pusan National University, Longevity Life Science and Technology Institutes, Pusan National University, Busan, Korea.
Kim
Ji Young
JY
Yu
Byung Pal
BP
Chung
Hae Young
HY
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D031204:Caloric Restriction; D002460:Cell Line; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D051858:Forkhead Transcription Factors; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D000071161:Forkhead Box Protein O1
D017931:DNA Primers; D051858:Forkhead Transcription Factors; D007328:Insulin; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1