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

M show a highly versatile phenotype depending on the receiving microenvironmental stimuli. M phenotypes are grouped in three subcategories. One is classically activated M (after stimulation with LPS or IFN-), and two are alternatively activated forms, known as woundhealing M (induced by IL-4/IL-13) and regulatory M (induced by IL-10/TGF-). Besides cytokines, hypoxia defines M 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 M. HIF target genes (such as ADM), analyzed in alternatively activated M from WT and HIF / mice, were regulated predominantly by HIF-1 and consistently showed reduced hypoxic induction in M stimulated with IL-4. To gain mechanistic insights, we analyzed HIF expression in polarized M. Classically activated M are characterized by the induction of HIF-1 but reduction of HIF-2 mRNA and protein, whereas wound-healing M decreased HIF-1 protein expression without altering mRNA levels. Analysis of protein stability and expression after proteasomal inhibition pointed to translational regulation of HIF-1 in wound-healing M. Following angiogenic-sprouting using embryonic stem cells exposed to supernatants of M incubated with IL-4 under hypoxia, shorter sprouts were revealed compared with supernatants of hypoxic M without IL-4. Conclusively, IL-4 reduces HIF-1 translation and thus, its activity in M and concomitantly, attenuates their ability to promote angiogenesis under hypoxic conditions. J. Leukoc. Biol. 95: 129–137; 2014.