Dexamethasone inhibits the LPS-induced activation of hypoxia-inducible factor 1 alpha (HIF-1α) in macrophages independently of the DUSP1-p38-TTP-HIF-1α regulatory axis.
The oxygen-sensitive transcription factor HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular and organism-level adaptations to decreasing oxygen availability. Under conditions of oxygen sufficiency HIF-1 is constitutively produced and degraded. In response to hypoxia, the degradation pathway is inhibited and HIF-1 protein accumulates via mechanisms that are now well understood. Additional signals combine with the oxygen-sensitive protein degradation pathway to modulate the expression and/or activity of HIF-1. In the context of the immune system, HIF-1 can be activated under normoxic conditions by a variety of stimuli, including the pro-inflammatory agonist lipopolysaccharide. Here we use a variety of genetic and pharmacological approaches to reveal that lipopolysaccharide-induced HIF-1 accumulation in primary macrophages is dependent on mitogen-activated protein kinase p38. This response is not dependent on modulation of HIF-1 protein stability: instead, it involves the phosphorylation and inactivation of tristetraprolin, an mRNA destabilizing protein that targets Hif1a mRNA for degradation. We previously reported that the glucocorticoid dexamethasone inhibits lipopolysaccharide-induced HIF-1 accumulation and metabolic reprograming in primary macrophages. Here we tested and disproved the hypothesis that dexamethasone prevents HIF-1 accumulation by inducing expression of dual specificity phosphatase 1 and thereby inhibiting p38 function. Hence two novel mechanisms critically regulate HIF-1 activation in lipopolysaccharide-treated macrophages: a p38-dependent mechanism that operates at the post-transcriptional level to control Hif1a mRNA expression, and a glucocorticoid-sensitive mechanism that operates at the post-translational level to control HIF-1 protein stability. Combined targeting of these two mechanisms may exert therapeutic effects in contexts where HIF-1 contributes to immune-mediated inflammatory pathology.