| Abstrakt: |
IL‐4 attenuates HIF‐1 activity by reducing HIF‐1α translation in MΦ, and concomitantly attenuates their ability to promote angiogenesis. 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. |
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