Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which 
are subsequently ingested to derive peptides for presentation to T cells in 
lymph nodes. To do so, DCs have to traverse many different tissues with varying 
oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in 
tumors, where vascularization is lacking, as well as in inflammatory foci, where 
oxygen is rapidly consumed by inflammatory cells during the respiratory burst. 
DCs respond to oxygen levels to tailor immune responses to such low-oxygen 
environments. In the present study, we identified a mechanism of 
hypoxia-mediated potentiation of release of tumor necrosis factor α (TNF-α), a 
pro-inflammatory cytokine with important roles in both anti-cancer immunity and 
autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this 
potentiation is controlled exclusively via the p38/mitogen-activated protein 
kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target 
gene of hypoxia-induced factor (HIF), a transcription factor controlled by 
oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression 
of MAP3K8 concomitant with the potentiation of TNF-α secretion. This 
potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a 
small molecule inhibitor of this kinase, and this also decreased p38/MAPK 
phosphorylation. However, expression of DC maturation markers CD83, CD86, and 
HLA-DR were not changed by hypoxia. Since DCs play an important role in 
controlling T-cell activation and differentiation, our results provide novel 
insight in understanding T-cell responses in inflammation, cancer, autoimmune 
disease and other diseases where hypoxia is involved.