FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages.
OBJECTIVE
Macrophages play an important role in the pathogenesis of insulin resistance via the production of proinflammatory cytokines. Our goal is to decipher the molecular linkage between proinflammatory cytokine production and insulin resistance in macrophages.


METHODS
We determined cytokine profiles in cultured macrophages and identified interleukin (IL)-1β gene as a potential target of FoxO1, a key transcription factor that mediates insulin action on gene expression. We studied the mechanism by which FoxO1 mediates insulin-dependent regulation of IL-1β expression in cultured macrophages and correlated FoxO1 activity in peritoneal macrophages with IL-1β production profiles in mice with low-grade inflammation or insulin resistance.


RESULTS
FoxO1 selectively promoted IL-1β production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1β promoter activity. Mutations of the FoxO1 binding site within the IL-1β promoter abolished FoxO1 induction of IL-1β expression. Macrophages from insulin-resistant obese db/db mice or lipopolysaccharide-inflicted mice were associated with increased FoxO1 production, correlating with elevated levels of IL-1β mRNA in macrophages and IL-1 protein in plasma. In nonstimulated macrophages, FoxO1 remained inert with benign effects on IL-1β expression. In response to inflammatory stimuli, FoxO1 activity was augmented because of an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion. This effect along with nuclear factor-κB acted to stimulate IL-1β production in activated macrophages.


CONCLUSIONS
FoxO1 signaling through nuclear factor-κB plays an important role in coupling proinflammatory cytokine production to insulin resistance in obesity and diabetes.
Su
Dongming
D
Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Coudriet
Gina M
GM
Hyun Kim
Dae
D
Lu
Yi
Y
Perdomo
German
G
Qu
Shen
S
Slusher
Sandra
S
Tse
Hubert M
HM
Piganelli
Jon
J
Giannoukakis
Nick
N
Zhang
Jian
J
Dong
H Henry
HH
D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology*; D053583:Interleukin-1beta / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology; D009765:Obesity / Q000503:physiopathology*
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B