title: IL-4 reduces the proangiogenic capacity of macrophages by down-regulating HIF-1α translation.
abstract: 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.
authors.affiliation: 1.Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. dehne@biochem.uni-frankfurt.de.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dehne
authors.forename: Michaela
authors.initials: M
authors.lastname: Tausendschön
authors.forename: Silke
authors.initials: S
authors.lastname: Essler
authors.forename: Theresa
authors.initials: T
authors.lastname: Geis
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmid
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D020033:Protein Isoforms
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D015847:Interleukin-4
keywords: classically activated; hypoxia; regulatory; wound healing