リポ多糖は、MAPK p38を介したmRNA安定化とデキサメタゾン感受性タンパク質安定化によりHIF-1αの蓄積を誘導する

In macrophages the hypoxia-inducible transcription factor HIF-1α can be activated under normoxic conditions by pro-inflammatory agonists such as lipopolysaccharide. This non-canonical HIF-1α activation allows macrophages to accommodate rapidly changing demands for energy and biosynthetic precursors in the face of an immune challenge. Alterations in HIF-1α hydroxylation and proteolysis have been implicated in the response, but the involvement of other signaling mechanisms and pathways is unclear. Here we use genetic and pharmacological approaches to show that lipopolysaccharide-induced HIF-1α accumulation in primary macrophages is dependent on mitogen-activated protein kinase p38 and mediated by 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-1α accumulation and metabolic reprograming in primary macrophages. Here we tested and disproved the hypothesis that dexamethasone exerts this effect via the MAPK p38 inactivator dual specificity phosphatase 1. Hence two novel mechanisms critically regulate HIF-1α activation in lipopolysaccharide-treated macrophages: a p38-dependent mechanism that operates at the post-transcriptional level to control Hif1a mRNA stability, and a glucocorticoid-sensitive mechanism that operates at the post-translational level to control HIF-1α protein stability. Combined targeting of these two mechanisms may exert therapeutic effects in contexts where HIF-1α contributes to immune-mediated inflammatory pathology.