FoxO1 Links Insulin Resistance to Proinflammatory Cytokine IL-1β Production in Macrophages

  1. Dongming Su1,
  2. Gina M. Coudriet1,
  3. Dae Hyun Kim1,
  4. Yi Lu2,
  5. German Perdomo1,
  6. Shen Qu1,
  7. Sandra Slusher1,
  8. Hubert M. Tse1,
  9. Jon Piganelli1,
  10. Nick Giannoukakis1,
  11. Jian Zhang2 and
  12. H. Henry Dong1
  1. 1Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania;
  2. 2Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  1. Corresponding author: H.H. Dong, dongh{at}pitt.edu.

Abstract

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.

RESEARCH DESIGN AND 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-1β 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received February 18, 2009.
    • Accepted July 18, 2009.
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  1. Diabetes vol. 58 no. 11 2624-2633
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