Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do!

Abstract

Maintenance of oxygen homoeostasis is the basic principle in cell proliferation, differentiation, survival, and function in all higher organisms. The transcription factor, HIF (hypoxia inducible factor) has a central role in oxygen homoeostasis, and is indispensably linked to energy metabolism. Abnormally reduced oxygen concentrations leading to dysfunctional cell metabolism are found in rheumatoid arthritis and hence, knowledge of the molecular adaptive responses to hypoxia and the involvement of HIF in the pathogenesis of RA are interesting.

Figure 1

Transcriptionally influenced direct targets of HIF. Gene products, which are directly activated by HIF at the transcriptional level, are shown. So far more than 60 HIF target genes have been identified by binding of HIF to hypoxia responsive elements in association with transcriptional control sequences. These HIF target genes promote erythropoiesis, angiogenesis, vasodilatation, and a switch to a glycolytic cell metabolism, resolving and counteracting hypoxic conditions.

Figure 2

Domain structure of HIF-1α and interacting factors. Domains: NLS, nuclear localisation signal; bHLH, basic helix-loop-helix (DNA binding and dimerisation); PAS, Per/Ahr-ARNT/Sim (dimerisation); PAC, PAS associated C-terminal domain; NTAD, N-terminal transactivation domain (transcriptional transactivation); CTAD, C-terminal transactivation domain (transcriptional transactivation); Factors: PHD, HIF prolyl hydroxylase; ARD1, ADP-ribosylation factor domain; FIH, factor inhibiting HIF; pVHL, von Hippel-Lindau tumour suppressor protein.

Figure 3

Structural alignment of human HIF-1/2/3α subunits and their isoforms. Functional domains are illustrated as boxes of various shades: bHLH, basic helix-loop-helix; PAS, Per/Ahr-ARNT/Sim; PAC, PAS associated C-terminal domain; NTAD, N-terminal transactivation domain; CTAD, C-terminal transactivation domain; ODD, oxygen dependent degradation domain. Figures in square brackets are references.

Figure 4

Oxygen dependent HIF regulation. HIFα targeting for proteasomal degradation under normoxic conditions (left side); hypoxic stabilisation of HIFα and recruitment of transcriptional coactivators (right side). FIH, factor inhibiting HIF-1.

Figure 5

Factors inducing HIF transactivation activity. Cytokines: interleukin 1ß (IL1ß), tumour necrosis factor α (TNFα); hormones: insulin, thyroid hormone, follicle stimulating hormone (FSH), angiotensin II, and thrombin; hypoxia, low pH level (acidosis), heat (fever); reactive oxygen species (ROS) and reactive nitrogen species (RNS): hydroxyl radicals (–OH*), superoxide anions (–O₂*^–), hydrogen peroxide (H₂O₂), singlet oxygen (¹O₂), nitric oxide (NO), nitrous acid (HNO₂), and nitrogen dioxide (NO₂); bacterium and virus related: lipopolysaccharide (LPS), hepatitis B virus protein X (HBx); growth factors: basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), insulin-like growth factor-I and -II (IGF-I/II), platelet derived growth factor-BB (PDGF-BB), and heregulin.

Figure 6

Hormone, cytokine, and growth factor mediated signalling to regulate HIF-1α protein expression and transcriptional transactivation activity. Hormones like insulin, cytokines like tumour necrosis factor (TNFα) and interleukin 1ß (IL1ß), as well as growth factors like transforming growth factor ß (TGFß) and fibroblast growth factor 2 (FGF2) can induce HIF-1 target genes even under normoxic conditions. Binding of these factors to their receptors activates intracellular signalling cascades by kinase mediated phosphorylation. One activated cascade is the phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B)/FK506 binding protein12-rapamycin associated protein leading to an increased HIF-1α mRNA translation, sufficient for its stabilisation. A negative regulator of the PI3K/AKT/FRAP cascade is the tumour suppressor protein PTEN, a phosphatase, which abolishes AKT activation. A second pathway involved in HIF-1 signalling is the RAF/MEK/MAPK pathway, leading to an enhancement of transcriptional activity of HIF-1α. Both pathways can be stimulated by the small GTP binding protein RAS.