Role of hypoxia inducible factor–1α for interferon synthesis in mouse dendritic cells

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Abstract

Dendritic cells (DCs) are an important link between innate and adaptive immunity. DCs get activated in inflamed tissues where oxygen tension is usually low, which requires the transcription factor hypoxia induc–ible factor (HIF)–1 for cellular adaptation. To investigate whether the HIF–1 transcriptional complex plays a pivotal role in the function of DCs, we compared the effects of exogenous inflammatory stimuli and hypoxia on HIF– 1αin bone marrow–derived DCs from wild type and myeloid– specific HIF–1 α knock–out mice. We showed that the Toll–like receptor ligands lipopolysaccharides and cytosine– phosphatidyl–guanines significantly induce HIF–1α mRNA and protein, leading to elevated HIF–1 target gene expression of vascular endothelial growth factor. In contrast, polyinosinic:polycytidylic acid did not show comparable effects. Furthermore the potential to up–regulate inflammatory cytokines critically influences DC function. Our data demonstrate that HIF–1αprotein is needed for adequate production of interferon–αand –β. In co–cultures of DCs and cytotoxic T cells, we observed that DCs lacking active HIF–1αprotein induce significantly less CD278 and granzyme B mRNA in T cells. We conclude that HIF– 1α plays a crucial role in DC interferon production and T cell activation, linking the innate and adaptive immune system.

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