Multinutrient undernutrition dysregulates the resident macrophage proinflammatory cytokine network, nuclear factor-κB activation, and nitric oxide production

Gregory M. Anstead, Bysani Chandrasekar, Qiong Zhang, Peter C. Melby

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

We have described previously a murine model of multinutrient undernutrition that reproduced the features of moderate human malnutrition and led to increased early dissemination of Leishmania donovani. Peritoneal cells from these malnourished mice produced decreased NO after stimulation with IFN-γ/LPS. We hypothesized that malnutrition may cause a deficit in NF-κB activation, a principal transcription pathway for inducible NO synthase and proinflammatory cytokines. Macrophages from malnourished mice, stimulated with IFN-γ/LPS, showed increased IL-6 production and decreased IL-10 and TNF-α production. Neutralization of TNF-α in macrophage cultures from the control mice mimicked the effect of malnutrition on NO and IL-10 production, whereas supplemental TNF-α added to cultures of macrophages from malnourished mice increased NO secretion. NF-κB nuclear binding activity in macrophages from the malnourished mice was reduced early after stimulation, but increased to supranormal values by 16- or 24-h poststimulation. Blocking NO production in the macrophages from the control mice reproduced the effect of malnutrition on the late activation of NF-κB, whereas supplemental NO decreased the late NF-κB activation in the malnourished mice. Thus, in macrophages from the malnourished mice, initial deficits in NF-κB activity probably lead to decreased TNF-α, which results in decreased NO; however, IL-6 is regulated independently from NF-κB and TNF-α. The late activation of NF-κB in the macrophages from malnourished mice is due to absence of negative feedback from NO.

Original languageEnglish (US)
Pages (from-to)982-991
Number of pages10
JournalJournal of Leukocyte Biology
Volume74
Issue number6
DOIs
StatePublished - Dec 1 2003

Keywords

  • Immunodeficiency
  • Interleukin-10
  • Interleukin-6
  • Transcription factor
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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