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

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