IL-4 reduces the proangiogenic capacity of macrophages by down-regulating HIF-1α translation

J Leukoc Biol. 2014 Jan;95(1):129-37. doi: 10.1189/jlb.0113045. Epub 2013 Sep 4.


MΦ show a highly versatile phenotype depending on the receiving microenvironmental stimuli. MΦ phenotypes are grouped in three subcategories. One is classically activated MΦ (after stimulation with LPS or IFN-γ), and two are alternatively activated forms, known as wound-healing MΦ (induced by IL-4/IL-13) and regulatory MΦ (induced by IL-10/TGF-β). Besides cytokines, hypoxia defines MΦ functions, as shown for classically activated cells. Yet, little is known about the role of hypoxia and HIF-1 and -2 in wound-healing or regulatory MΦ. HIF target genes (such as ADM), analyzed in alternatively activated MΦ from WT and HIF-/- mice, were regulated predominantly by HIF-1 and consistently showed reduced hypoxic induction in MΦ stimulated with IL-4. To gain mechanistic insights, we analyzed HIF expression in polarized MΦ. Classically activated MΦ are characterized by the induction of HIF-1α but reduction of HIF-2α mRNA and protein, whereas wound-healing MΦ decreased HIF-1α protein expression without altering mRNA levels. Analysis of protein stability and expression after proteasomal inhibition pointed to translational regulation of HIF-1α in wound-healing MΦ. Following angiogenic-sprouting using embryonic stem cells exposed to supernatants of MΦ incubated with IL-4 under hypoxia, shorter sprouts were revealed compared with supernatants of hypoxic MΦ without IL-4. Conclusively, IL-4 reduces HIF-1α translation and thus, its activity in MΦ and concomitantly, attenuates their ability to promote angiogenesis under hypoxic conditions.

Keywords: classically activated; hypoxia; regulatory; wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Hypoxia
  • Cell Line
  • Cytokines / pharmacology
  • Gene Expression Regulation / drug effects
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Interleukin-4 / pharmacology*
  • Macrophage Activation / drug effects
  • Macrophage Activation / immunology
  • Macrophages / drug effects*
  • Macrophages / metabolism*
  • Mice
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / physiology*
  • Protein Biosynthesis / drug effects*
  • Protein Isoforms


  • Cytokines
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protein Isoforms
  • Interleukin-4