Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization

J Neurochem. 2008 Apr;105(2):296-307. doi: 10.1111/j.1471-4159.2007.05129.x. Epub 2007 Nov 16.


Recognition of lipopolysaccharide (LPS), the endotoxin of gram-negative bacteria, by microglia occurs through its binding to specific receptors, cluster of differentiation 14 and toll-like receptor-4. LPS binding to these receptors triggers the synthesis of proinflammatory cytokines that coordinate the brain innate immune response to protect the CNS of the infection. Docosahexaenoic acid (DHA), a n-3 polyunsaturated fatty acid highly incorporated in the brain, is a potent immunomodulator. In this study, we investigated whether DHA modulates LPS receptor localization and, as a consequence, LPS-induced signaling pathway and proinflammatory cytokine production. We demonstrated that DHA, when added exogenously, is specifically enriched in membrane phospholipids, but not in raft lipids of microglial cells. DHA incorporation in membrane impaired surface presentation of LPS receptors cluster of differentiation 14 and toll-like receptor-4, but not their membrane subdomain localization. LPS-induced nuclear factor kappa B activation was inhibited by DHA, hence, LPS-induced proinflammatory cytokine synthesis of interleukin-1beta and tumor necrosis factor alpha was strongly attenuated. We suggest that DHA is highly anti-inflammatory by targeting LPS receptor surface location, therefore reducing LPS action on microglia. This effect represents a new insight by which DHA modulates in the brain the expression of proinflammatory cytokines in response to bacterial product.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Cell Line, Transformed
  • Cytokines / metabolism*
  • Docosahexaenoic Acids / pharmacology*
  • Down-Regulation / drug effects
  • Drug Interactions
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry / methods
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharide Receptors / physiology*
  • Lipopolysaccharides / pharmacology*
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / physiology
  • Mice
  • Microglia / drug effects*
  • Protein Structure, Tertiary / physiology
  • Protein Transport / drug effects
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha


  • Cytokines
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Docosahexaenoic Acids