Abstract
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.
Highlights
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases
In this review we focused on the role of tumor necrosis factor-α (TNF-α) and IL-1β in the regulation of the hypoxia-inducible factor (HIF) pathway
While previous studies have suggested that the intermediatory role of IL-1β involves biological activation of the mitogen-activated protein kinase (MAPK) signaling pathway, Stiehl et al [54] described the downregulatory effect of MAPKKs inhibitors, PD 98059 and U0126, on IL-1β-induced HIF-1α accumulation and HIF-1 DNA-binding in HepG2 cells [54]
Summary
Eukaryotic cells generate metabolic energy currency within mitochondria in the form of adenosine triphosphate (ATP), utilizing molecular oxygen (O2 ) as the final electron acceptor in the oxidative metabolism of glucose (oxidative phosphorylation) [1]. Cells require a continuous O2 supply in order to maintain bioenergetic homeostasis. Tissue oxygenation homeostasis is determined by a balance of O2 consumption by mitochondria and oxygen supply by erythrocytes in capillaries [2]. Hypoxia is the condition which arises when the cellular O2 demand required to generate sufficient levels of ATP to support physiological requirements exceeds the available supply. This can be as a result of an increased O2 demand and/or decreased supply to the tissue. Hypoxia can occur in a range of pathological diseases including inflammation, cardiovascular disease, and cancer, where oxygen demand is enhanced or oxygen supply is diminished [4].
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