Hypoxia-inducible factors (HIF) is an important nuclear transcription factor that regulates the target gene. The heterodimeric HIF transcription factors consist of HIF-α and HIF-β, that form functional HIFs. Mammals contain HIF-1α, HIF-2α, and HIF-3α. It is closely related to biological behaviors such as glucose metabolism, cell proliferation, angiogenesis and cell invasion.
The transcription factor HIF-1α was first identified in 1995and, since its detection, it has been associated with several types of disease from cancer to infection. Cells under oxygen levels lower than physiological undertake a diversity of biological responses in order to adapt to these critical conditions. Hypoxic cells respond by increasing the expression of various genes that will help survival under these situations. The main cellular response manager to low oxygen levels is HIF-1α3, 4. Upon hypoxia, cells react by increasing the expression of genes encoding proteins that facilitate oxygen supply (e.g., erythropoietin, VEGF) or improve anaerobic production of energy (e.g., glycolytic enzymes).
The importance of HIF-1α in mammalian development can be seen by noting that its absence is lethal for embryogenesis, in part because of defective vascularization. HIF-1α activation can have adaptive roles in a diversity of pathological conditions: HIF-1α allows revascularization after cardiac and cerebral ischemia, but it also favors tumor growth in hypoxic environments by promoting angiogenesis and metabolic adaptations to hypoxia.
Another relevant finding is that HIF-1α pathway is present in almost all cell types and all higher eukaryotes. HIF complex supports the expression of genes such as erythropoietin (EPO) by binding to hypoxia-responsive enhancer elements (HREs).
HIF-1α activity is closely regulated by oxygen-dependent control of the cell. In oxygenated states, HIF-1α is quickly degraded in an ubiquitin dependent way and its degradation is mediated by hydroxylation on Pro-402 and −564. HIF acts on late cell death induced by hypoxia. HIF-1α activates late death in cortical neurons by a p53-dependent pathway, thus defining an important regulating element of ischemic cell death.
The hypoxic response is important for the function of tissue macrophages and infiltrating neutrophils that find low O2 pressure in infected tissues. HIF-1α was also suggested to promote expression of inflammatory cytokines in macrophages stimulated with LPS to induce cytokines production through the regulation of NF-kB.
A recent study has suggested that HIF-1α activation can also occur in response to infections with human pathogens.
HIF-1α may mediate the functional reprogramming of monocytes in sepsis. During human sepsis efficient plasticity of monocytes occurs, wherein they changed from a pro-inflammatory to an immunosuppressive phenotype, while enhancing protective actions like antimicrobial activity, phagocytosis and tissue remodeling. This phenomenon signals the potential path of its therapeutic use as a regulator of human sepsis.
HIF-1α is a decisive determinant of sepsis phenotype through the production of inflammatory cytokines, including IL-l, IL-4, IL-6, IL-12 and TNF-α. Excess cytokines may be harmful to the host during early sepsis. HIF-1α deletion in macrophages is protective against LPS-induced mortality and HIF is protective against mortality, also preventing clinical progress to hypotension and hypothermia.
HIF-1α activation leads to secretion of VEGF that increase markedly the vascular permeability. Inflammation and infection are associated with increased vascular permeability with tissue edema and vascular leakage ending in septic shock. This dangerous clinical condition might be caused by bacterial-induced HIF-1α activation and by VEGF. Therefore, it is not surprising that neutralization of HIF-1α-regulated VEGF results in intense decrease of vascular permeability and mortality in sepsis. Several HIF-1α-regulated genes have been associated with protection of vascular barrier function during inflammation and hypoxia.
Infections with the angiogenic bacterium Bartonella henselae (bacillary angiomatosis disease) result in HIF-1α activation both in vitro and in vivo, probably via hypoxia-associated metabolic alterations. Activation of HIF-1α by human pathogenic Enterobacteriaceae seems to follow a more general pattern of bacterial infections including the induction of iron deficiency in host cells by bacterial siderophores due to a hypoxia-independent HIF-1α activation.
Hepatitis C virus (HCV) protein triggers HIF-1α by normoxic stabilization of its subunit. The expression of HIF-controlled genes is significantly up-regulated including those coding for glycolytic enzymes.
Toxoplasma gondii is an obligate intracellular protozoan pathogen. Some studies have presented that genes mediating cellular responses to hypoxia were up-regulated in Toxoplasma-infected cells but not in cells infected with Trypanosoma cruzi, another intracellular pathogen. Expression of these genes is controlled by HIF-1α.
Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive pulmonary aspergillosis (IPA) in immunocompromised individuals, particularly in hematopoietic stem cell transplant recipients and patients with acute leukemia. As a new treatment approach for infectious diseases, HIF-1α is presently being considered as a possible pharmacological target for host immune defense.
Recently studies in rats and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury, with hypoxia inducible factor (HIF)-2α playing a major role. In response to the reflux of acid and bile, HIF-2α in esophageal epithelial cells becomes stabilized, thereby increasing production of pro-inflammatory cytokines that attract T lymphocytes and other inflammatory cells to damage the esophagus. Recent studies have identified small molecule inhibitors of HIF-2α that demonstrate exquisite isoform selectivity, and clinical trials for treatment of HIF-2α-driven kidney cancers are ongoing. It is conceivable that a HIF-2α-directed therapy might be a novel approach to prevention and treatment of reflux esophagitis.