Nitro-oleic acid regulates growth factor-induced differentiation of bone marrow-derived macrophages

Free Radic Biol Med. 2017 Mar;104:10-19. doi: 10.1016/j.freeradbiomed.2017.01.003. Epub 2017 Jan 4.


Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO2-FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO2-OA for different times. RAW 264.7 macrophages were used for short-term (1-5min) experiments. We discovered that NO2-OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO2-OA acts via downregulation of signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO2-OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO2-OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO2-OA regulates the process of macrophage differentiation and that NO2-FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues.

Keywords: Differentiation; Growth factors; Inflammation; Macrophages; Nitro-fatty acids; Nitro-oleic acid; Signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / drug effects
  • Cell Differentiation / drug effects
  • Colony-Stimulating Factors / genetics*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Inflammation / drug therapy*
  • Inflammation / genetics
  • Inflammation / pathology
  • MAP Kinase Signaling System / drug effects
  • Macrophages / drug effects
  • Mice
  • Nitric Oxide / administration & dosage*
  • Nitric Oxide / chemistry
  • Oleic Acid / administration & dosage*
  • Oleic Acid / chemistry
  • Phosphatidylinositol 3-Kinases / genetics
  • RAW 264.7 Cells
  • STAT5 Transcription Factor / genetics


  • Colony-Stimulating Factors
  • STAT5 Transcription Factor
  • Oleic Acid
  • Nitric Oxide
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases