JOURNAL OF INTERFERON & CYTOKINE RESEARCH 25:297–310 (2005)
© Mary Ann Liebert, Inc.
Hypoxia-Inducible Factor-1 (HIF-1): A Novel Transcription
Factor in Immune Reactions
THOMAS HELLWIG-BÜRGEL,
1
DANIEL P. STIEHL,
2
ANIKA E. WAGNER,
1
ERIC METZEN,
1
and WOLFGANG JELKMANN
1
ABSTRACT
Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional complex that has been recognized primarily
for its role in the maintenance of oxygen and energy homoeostasis. The HIF-1 subunit is O
2
labile and is de-
graded by the proteasome following prolyl-hydroxylation and ubiquitination in normoxic cells. The present
review summarizes evidence that HIF-1 is also involved in immune reactions. Immunomodulatory peptides,
including interleukin-1 (IL-1) and tumor necrosis factor- (TNF-), stimulate HIF-1 dependent gene expres-
sion even in normoxic cells. Both the hypoxic and the cytokine-induced activation of HIF-1 involve the phos-
phatidylinositol-3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) signaling pathways. In ad-
dition, heat shock proteins (HSP) and other cofactors interact with HIF-1 subunits. HIF-1 increases the
transcription of several genes for proteins that promote blood flow and inflammation, including vascular en-
dothelial growth factor (VEGF), heme oxygenase-1, endothelial and inducible nitric oxide synthase (NOS) and
cyclooxygenase-2 (COX-2). The pharmacologic activation of the HIF-1 complex can be desirable in ischemic
and inflammatory disorders. In contrast, HIF-1 blockade may be beneficial to prevent tumor angiogenesis
and tumor growth.
297
INTRODUCTION
T
HE HYPOXIA-INDUCIBLE transcription factor-1 (HIF-1) was
originally discovered as a biologic O
2
sensor that enables
the organism to adapt to hypoxia. Under hypoxic conditions,
the rate of O
2
supply limits the rate of O
2
consumption, and
aerobic metabolism is reduced. In cases of severe O
2
deficiency,
the respiratory chain succumbs, and as a consequence, cellular
death may result. Thus, it is important that HIF-1 promotes the
expression of genes that encode proteins that increase the cel-
lular supply with O
2
and with energy-providing substrates.
(1,2)
HIF-1 initiates the defense against hypoxia at different levels.
In kidney and liver, hypoxia induces the synthesis of erythro-
poietin (EPO),
(3,4)
which stimulates erythropoiesis, thereby in-
creasing the O
2
capacity of the blood.
(5)
In virtually all tissues,
hypoxia induces the synthesis of proteins controlling local blood
flow, such as vascular endothelial growth factor (VEGF),
(6,7)
endothelial nitrix oxide synthase (eNOS),
(8)
and heme oxyge-
nase-1 (HOX-1).
(9)
VEGF stimulates angiogenesis and in-
creases the permeability of blood vessels.
(10)
eNOS and
HOX-1 generate NO and carbon monoxide (CO), which are
potent vasodilatory substances that augment perfusion of the
hypoxic tissue. At the cellular level, hypoxia induces the ex-
pression of virtually all glycolytic enzymes, including phos-
phoglycerate kinase-1 (PGK-1), enolase 1, and lactate dehy-
drogenase-1 (LDH-1).
(11,12)
Furthermore, the expression of
membraneous glucose transporters (primarily GLUT-1) is in-
creased under hypoxic conditions, thereby alleviating glucose
uptake to provide substrate for glycolysis.
(13,14)
To promote
gene expression of all of these proteins, HIF-1 binds to hypoxia-
responsive elements (HREs) present in promoter or enhancer
DNA regions.
(15)
Recent studies have shown that HIF-1 plays a central role in
stress responses beyond hypoxia. A number of peptidic and non-
peptidic mediators of inflammation can activate HIF-1 even un-
der normoxic conditions.
(16,17)
Moreover, HIF-1 stimulates the
expression of several genes encoding proteins that promote in-
flammatory reactions. Apart from VEGF and HOX-1, among
these proteins are the inducible NOS (iNOS)
(18)
and cyclooxy-
genase-2 (COX-2) (for references, see ref. 2). Thus, HIF-1 is a
1
Institute of Physiology, University of Luebeck, D-23538 Luebeck, Germany.
2
Physiologisches Institut der Universität Zürich, CH-8057 Zürich, Switzerland.
REVIEW