Pulmonary and Critical Care Division, Department of Medicine, New England Medical Center/Tupper Research Institute, Tufts University School of Medicine, Boston, Massachusetts 02111
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ABSTRACT |
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Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. When cellular production of ROS overwhelms its antioxidant capacity, damage to cellular macromolecules such as lipids, protein, and DNA may ensue. Such a state of "oxidative stress" is thought to contribute to the pathogenesis of a number of human diseases including those of the lung. Recent studies have also implicated ROS that are generated by specialized plasma membrane oxidases in normal physiological signaling by growth factors and cytokines. In this review, we examine the evidence for ligand-induced generation of ROS, its cellular sources, and the signaling pathways that are activated. Emerging concepts on the mechanisms of signal transduction by ROS that involve alterations in cellular redox state and oxidative modifications of proteins are also discussed.
redox signaling; growth factors; cytokines; oxidation-reduction; free radicals
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INTRODUCTION |
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ALL MULTICELLULAR ORGANISMS depend on highly complex networks of both extracellular and intracellular signals to orchestrate cell-cell communication in diverse physiological processes such as developmental organogenesis, maintenance of normal tissue homeostasis, and repair responses to tissue injury. Typically, extracellular signals are composed of growth factors, cytokines, hormones, and neurotransmitters that bind to specific cell surface receptors. These receptor-ligand interactions then generate various types of intracellular signals that may involve changes in ion concentrations (ion channel-linked receptors), activation of trimeric GTP-binding regulatory proteins (G protein-coupled receptors), and activation of receptor kinases (enzyme-linked receptors). Downstream signaling is then relayed by second messengers (such as cAMP, Ca2+, and phospholipid metabolites) and by protein phosphorylation cascades. Ultimately, these intracellular signaling pathways lead to the activation of transcription factors that regulate the expression of specific sets of genes essential for diverse cellular functions.
Molecular oxygen (dioxygen; O2) is essential for the
survival of all aerobic organisms. Aerobic energy metabolism is
dependent on oxidative phosphorylation, a process by which the
oxidoreduction energy of mitochondrial electron transport (via a
multicomponent NADH dehydrogenase enzymatic complex) is converted to
the high-energy phosphate bond of ATP. O2 serves as the
final electron acceptor for cytochrome-c oxidase, the
terminal enzymatic component of this mitochondrial enzymatic complex,
that catalyzes the four-electron reduction of O2 to
H2O. Partially reduced and highly reactive metabolites of
O2 may be formed during these (and other) electron transfer
reactions. These O2 metabolites include superoxide anion (O2·) and hydrogen peroxide
(H2O2), formed by one- and two-electron reductions of O2, respectively. In the presence of
transition metal ions, the even more reactive hydroxyl radical (OH·)
can be formed. These partially reduced metabolites of O2
are often referred to as "reactive oxygen species" (ROS) due to
their higher reactivities relative to molecular O2.
ROS from mitochondria and other cellular sources have been
traditionally regarded as toxic by-products of metabolism with the
potential to cause damage to lipids, proteins, and DNA
(78). To protect against the potentially damaging effects
of ROS, cells possess several antioxidant enzymes such as superoxide
dismutase (which reduces O2· to
H2O2), catalase, and glutathione peroxidase
(which reduces H2O2 to H2O). Thus
oxidative stress may be broadly defined as an imbalance between
oxidant production and the antioxidant capacity of the cell to prevent
oxidative injury. Oxidative stress has been implicated in a large
number of human diseases including atherosclerosis, pulmonary fibrosis,
cancer, neurodegenerative diseases, and aging (56, 103).
Yet the relationship between oxidative stress and the pathobiology of
these diseases is not clear, largely due to a lack of understanding of
the mechanisms by which ROS function in both normal physiological and
disease states.
Accumulating evidence suggests that ROS are not only injurious
by-products of cellular metabolism but also essential participants in
cell signaling and regulation (76, 237). Although this
role for ROS is a relatively novel concept in vertebrates, there is strong evidence of a physiological role for ROS in several nonmammalian systems. In bacteria, the OxyR protein functions as a transcriptional regulator of H2O2-inducible genes and has been
shown to be directly activated by oxidation (53, 278). A
recent study (324) has shown that
H2O2 oxidizes two conserved cysteines in OxyR
to form intramolecular disulfide linkages that trigger the activation of this transcription factor, presumably by changing its conformation. The Escherichia coli SoxR transcription factor is activated
specifically in response to O2·-generating
redox-cycling agents such as paraquat and menadione (95).
Activated SoxR mediates SoxS gene transcription, resulting in an increase in SoxS protein that then activates the transcription of
several other genes including superoxide dismutase (SOD)
(63). SoxR is a homodimer that contains two redox-active
iron-sulfur [2Fe-2S] centers that are sensitive to oxidation by
O2
· (109, 312). The iron-sulfur
centers of SoxR must be in their oxidized state for them to be
transcriptionally active (85), thus providing a plausible
mechanism by which O2
· transmits its gene
regulatory signal. In plant cells, generation of
H2O2 in response to various pathogens elicits
localized cell death to limit spread of the pathogen (165)
and a more systemic response involving the induction of defense genes
regulating plant immunity (10). In sea urchins,
fertilization triggers extracellular production of
H2O2 by a plasma membrane oxidase with the
simultaneous release of ovoperoxidase (263). Peroxidase-
or H2O2-catalyzed cross-linking of
extracellular proteins then forms a protective envelope around the
freshly fertilized oocyte.
The apparent paradox in the roles of ROS as essential biomolecules in
the regulation of cellular functions and as toxic by-products of
metabolism may be, at least in part, related to differences in the
concentrations of ROS produced. This is analogous to the effects of
nitric oxide (NO·), which has both regulatory functions and cytotoxic
effects depending on the enzymatic source and relative amount of NO·
generated (210). NO· functions as a signaling molecule mediating vasodilation when produced in low concentrations by the
constitutive isoform of nitric oxide synthase (NOS) in vascular endothelial cells (309) and as a source of highly toxic
oxidants utilized for microbicidal killing when produced in high
concentrations by inducible NOS in macrophages (178).
Indeed, all phagocytic cells have a well-characterized
O2·-generating plasma membrane oxidase capable of
producing the large amounts of ROS required for its function in host
defense. In this review, we examine the evidence for the presence of
similar plasma membrane oxidases that generate much lower amounts of
ROS in nonphagocytic cells for purposes of cell signaling and
regulation. We summarize the cellular effects of a wide range of
ligand-receptor interactions that have been shown to generate
intracellular or extracellular ROS. Emerging concepts on the mechanisms
by which ROS may function as signaling molecules are discussed. For
purposes of this review, we focus primarily on the cellular effects of ligand-mediated (endogenous) production of ROS rather than on the
effects of exogenous oxidative stress. Also, the role of NO· as a
signaling molecule is not discussed here except in the context of its
ability to interact with and modulate O2
· signaling.
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CHEMISTRY OF ROS |
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The biological chemistries of ROS primarily determine the ability
of different species to react with specific cellular substrates within
the microenvironment in which they are produced. These ROS-substrate
reactions are likely to form the basis for our understanding of ROS
specificity and their mechanisms of action. ROS have often been
"loosely" categorized as free radicals, but this is incorrect because not all ROS are free radicals. A free radical is defined as any
atomic or molecular species capable of independent existence that
contains one or more unpaired electrons in one of its molecular orbitals (102). Molecular O2 itself qualifies
as a free radical because it has two unpaired electrons with parallel
spin in different -antibonding orbitals. This spin restriction
accounts for its relative stability and paramagnetic properties.
O2 is capable of accepting electrons to its antibonding
orbitals, becoming "reduced" in the process, and, therefore,
functioning as a strong oxidizing agent.
A one-electron reduction of O2 results in the formation of
O2· either by enzymatic catalysis or by "electron
leaks" from various electron transfer reactions.
O2
· chemistry in aqueous solution differs greatly
from that in organic solvents. In contrast to its remarkable stability
in many organic solvents, O2
· in aqueous solution
is short-lived. This "instability" in aqueous solutions is based on
the rapid dismutation of O2
· to
H2O2, a reaction facilitated by higher
concentrations of the protonated form of O2
·
(HO2·) in more acidic pH conditions. Thus the dismutation
reaction has an overall rate constant of 5 × 105
M
1 · s
1 at pH 7.0. SOD speeds up
this reaction almost 104-fold (rate constant = 1.6 × 109
M
1 · s
1) (79). This
implies that any reaction of O2
· in aqueous
solution will be in competition with SOD or, in its absence, with the
spontaneous dismutation reaction itself. NO· reacts with
O2
· at near diffusion-limited rates and is,
therefore, one of the few biomolecules that is able to "outcompete"
SOD for O2
· (119). Thus in most
biological systems, unless sufficiently high concentrations of NO· or
other similarly reactive molecules are present, generation of
O2
· usually results in the formation of
H2O2.
Although dismutation of O2· probably accounts for
much of the H2O2 produced by eukaryotic cells,
H2O2 can also be formed by direct two-electron
reduction of O2, a reaction mechanism shared by a number of
flavoprotein oxidases (186). Unlike
O2
·, H2O2 is not a free
radical and is a much more stable molecule. H2O2 is able to diffuse across biological
membranes, whereas O2
· does not.
H2O2 is a weaker oxidizing agent than
O2
·. However, in the presence of transition metals
such as iron or copper, H2O2 can give rise to
the indiscriminately reactive and toxic hydroxyl radical (OH·) by
Fenton chemistry.
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CELLULAR SOURCES AND REGULATION OF ROS |
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Cellular production of ROS occurs from both enzymatic and
nonenzymatic sources. As stated earlier, any electron-transferring protein or enzymatic system can result in the formation of ROS as
"by-products" of electron transfer reactions. This "unintended" generation of ROS in mitochondria accounts for ~1-2% of total O2 consumption under reducing conditions (78).
Due to high concentrations of mitochondrial SOD, the intramitochondrial
concentrations of O2· are maintained at very low
steady-state levels (298). Thus unlike
H2O2, which is capable of diffusing across the
mitochondrial membrane into the cytoplasm (44),
mitochondria-generated O2
· is unlikely to escape
into the cytoplasm. The potential for mitochondrial ROS to mediate cell
signaling has gained significant attention in recent years,
particularly with regard to the regulation of apoptosis (25, 40,
46, 154, 166, 302). There is evidence to suggest that tumor
necrosis factor (TNF)-
- and interleukin (IL)-1-induced apoptosis may
involve mitochondria-derived ROS (269, 273, 311). It has
also been suggested that the mitochondria may function as an
"O2 sensor" to mediate hypoxia-induced gene transcription (45, 68).
The endoplasmic reticulum (ER) is another membrane-bound intracellular
organelle that, unlike mitochondria, is primarily involved in lipid and
protein biosynthesis. Smooth ER (lacking bound ribosomes) contains
enzymes that catalyze a series of reactions to detoxify lipid-soluble
drugs and other harmful metabolic products. The most extensively
studied of these are the cytochrome P-450 and b5 families of enzymes that can oxidize
unsaturated fatty acids and xenobiotics and reduce molecular
O2 to produce O2· and/or
H2O2 (18, 43, 78). Although there
does not appear to be a direct link between ER-derived oxidants and
growth factor signaling, there is evidence for redox regulation of
ER-related functions such as protein folding and secretion (22,
32, 120, 219). Bauskin et al. (32) showed that Ltk,
a nonreceptor tyrosine kinase (non-RTK) expressed mainly in
lymphocytes, leukemia cells, and neurons, is activated by forming
disulfide-linked multimers in response to thiol-oxidizing agents. It
has also been suggested that an O2
·-generating
microsomal NADH oxidoreductase may function as a potential pulmonary
artery O2 sensor in pulmonary artery smooth muscle cells
(198, 199).
Nuclear membranes contain cytochrome oxidases and electron transport systems that resemble those of the ER but the function of which is unknown (78, 102). It has been postulated that electron "leaks" from these enzymatic systems may give rise to ROS that can damage cellular DNA in vivo (102).
Peroxisomes are an important source of total cellular
H2O2 production (37). They contain
a number of H2O2-generating enzymes including
glycolate oxidase, D-amino acid oxidase, urate oxidase, L--hydroxyacid oxidase, and fatty acyl-CoA oxidase.
Peroxisomal catalase utilizes H2O2 produced by
these oxidases to oxidize a variety of other substrates in
"peroxidative" reactions (296). These types of
oxidative reactions are particularly important in liver and kidney
cells in which peroxisomes detoxify a variety of toxic molecules
(including ethanol) that enter the circulation. Another major function
of the oxidative reactions carried out in peroxisomes is
-oxidation
of fatty acids, which in mammalian cells occurs in mitochondria and
peroxisomes (9). Specific signaling roles have not been
ascribed to peroxisome-derived oxidants, and only a small fraction of
H2O2 generated in these intracellular organelles appears to escape peroxisomal catalase (37,
230).
In addition to intracellular membrane-associated oxidases, soluble
enzymes such as xanthine oxidase, aldehyde oxidase, dihydroorotate dehydrogenase, flavoprotein dehydrogenase and tryptophan dioxygenase can generate ROS during catalytic cycling (78). The most
extensively studied of these is the O2·-generating
xanthine oxidase, which can be formed from xanthine dehydrogenase after
tissue exposure to hypoxia (188, 222). Xanthine oxidase is
widely used to generate O2
· in vitro to study the
effect of ROS on diverse cellular processes; however, no studies have
implicated a direct physiological role for endogenous xanthine oxidase
in cell signaling.
Autooxidation of small molecules such as dopamine, epinephrine,
flavins, and hydroquinones can be an important source of intracellular ROS production (78). In most cases, the direct product of
such autooxidation reactions is O2·. Although there
is no known role for autooxidation of small molecules in growth factor
and/or cytokine signaling, such reactions may induce oxidative stress
and alter the overall cellular redox state. There is the suggestion
that the prooxidant effects of dopamine autooxidation may be involved
in the dopamine-induced apoptosis that is implicated in the
pathogenesis of neurodegenerative diseases such as Parkinson's disease
(214, 215, 320).
Plasma membrane-associated oxidases have been implicated as the sources
of most growth factor- and/or cytokine-stimulated oxidant production
(97, 143, 191, 253, 280, 293), although the precise
enzymatic sources have yet to be fully characterized. The best
characterized of the plasma membrane oxidases in general is the
phagocytic NADPH oxidase, which serves a specialized function in host
defense against invading microorganisms (reviewed in Refs. 20, 258). This multicomponent enzyme
catalyzes the one-electron reduction of O2 to
O2·, with NADPH as the electron donor through the
transmembrane protein cytochrome b558 (a
heterodimeric complex of gp91phox and
p22phox protein subunits). The transfer of
electrons occurs from NADPH on the inner aspect of the plasma membrane
to O2 on the outside. During phagocytosis, the plasma
membrane is internalized as the wall of the phagocytic vesicle, with
what was once the outer membrane surface now facing the interior of the
vesicle. This targets the delivery of O2
· and its
reactive metabolites internally for localized microbicidal activity
(20).
Recent studies (33, 81, 110, 127, 192, 200) have suggested
that functional components of the phagocytic NADPH are present in
nonphagocytic cells. Expression of p22phox has
been demonstrated in the adventitial smooth muscle cells of coronary
arteries (19) and the aorta (183). Moreover,
polymorphism of the p22phox gene has been
associated with an increased risk of coronary artery disease in young
Caucasian men (84). Increased aortic adventitial O2· production contributes to hypertension by
blocking the vasodilatory effects of NO· (305).
3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors appear to have a
"cardioprotective" role not only by their effect on lowering
cholesterol but also by inhibiting the activity of an
O2
·-generating oxidase in vascular endothelial
cells and, thereby, improving NO·-dependent vasodilation
(303). Angiotensin II (ANG II)-induced hypertension is
mediated, at least in part, by direct interactions between
O2
·, generated by a NAD(P)H oxidase, and NO· in
vascular smooth muscle cells (80).
p22phox has been shown to be a functional
component of this ANG II-stimulated oxidase (183, 322).
TNF-
also stimulates O2
· production in vascular
smooth muscle cells by a p22phox-based
NADH oxidase and appears to upregulate p22phox
gene expression in these cells (60). Both
gp91phox and p22phox are
expressed in pulmonary neuroepithelial cells where a NADPH oxidase-like
enzyme may function as an O2 sensor by activating O2- and H2O2-sensitive
K+ channels (304). However, it was later
demonstrated that mice with chronic granulomatous disease (lacking a
functional gp91phox subunit) have preserved
hypoxic vasoconstrictive responses and O2 sensing,
suggesting that this oxidase is not involved (14). More
recently, Suh et al. (279) demonstrated that
Mox-1, a gene encoding a homologue of the catalytic subunit
of the phagocytic gp91phox, is expressed in a
number of tissues including vascular smooth muscle. In this study,
Mox-1 expression in NIH/3T3 cells was associated with
increased O2
· production, serum-stimulated cell
growth, and a transformed phenotype. This study suggests that an
O2
·-generating oxidase similar (but not identical)
to the phagocytic NADPH oxidase is present in some nonphagocytic cells
where it functions primarily as a regulator of cellular growth responses.
Cytochrome b558, along with the cytosolic
components p67phox,
p47phox, and
p40phox, makes up the core protein
subunits of the phagocytic NADPH oxidase complex. Activation of the
oxidase, however, requires the additional participation of Rac2 (or
Rac1 in mouse macrophages) and Rap1A, members of the Ras superfamily of
small GTP-binding proteins. During activation, Rac2 binds GTP and
migrates to the plasma membrane along with the cytosolic components to
form the active oxidase complex. A requirement for Rac1 in the
activation of the mitogenic oxidase has also been demonstrated in
nonphagocytic cells (55, 128). The insert region in Rac1
(residues 124-135) appears to be essential for
O2· production and stimulation of mitogenesis in
quiescent fibroblasts but not for Rac1-induced cytoskeletal changes or
activation of Jun kinase (128).
Another GTP-binding protein, p21Ras, appears to function
upstream from Rac1 in oxidant-dependent mitogenic signaling (121,
281). Sundaresan et al. (281) showed that dominant
negative expression of Rac1 inhibits not only the growth factor-
and/or cytokine-generated rise in intracellular ROS in NIH/3T3 cells
but also the ROS production in cells overexpressing a
constitutively active isoform of Ras (H-RasV12). Stable
transfection of the same Ras plasmid (H-RasV12) in
fibroblasts induces cellular transformation and constitutive production
of large amounts of O2· (121). In this
study, mitogenic signaling in Ras-transformed fibroblasts was
demonstrated to be redox sensitive but independent of the
mitogen-activated protein (MAP) kinase (MAPK) or c-Jun NH2-terminal kinase (JNK) pathways. Results from our
laboratory (292) demonstrate the requirement for
p21Ras in the generation of intracellular
O2
· by mitogens such as platelet-derived growth
factor (PDGF)-BB, fibroblast growth factor (FGF)-2, and transforming
growth factor (TGF)-
in nontransformed human lung fibroblasts.
However, studies from our laboratory (292, 293) also
suggest the presence of a distinctly different ROS-generating enzymatic
system in these cells that is independent of p21Ras
regulation and that primarily generates extracellular
H2O2 in response to TGF-
1.
In contrast to these relatively recent reports of pyridine- and
flavin-linked oxidase activities in nonphagocytic cells, enzymes involved in phospholipid metabolism have been known to exist for several decades. Membrane phospholipids, in addition to their structural role in providing membrane integrity, are substrates for the
action of the phospholipases (PLs) PLA2, PLC, and PLD. Although these enzymes are important for the generation of lipid second
messengers, they have generally not been associated with ROS production
in nonphagocytic cells. A recent report by Touyz and Schiffrin
(297), however, suggests that ANG II-induced
O2· production in smooth muscle cells is dependent
on the PLD pathway.
PLA2 hydrolyzes phospholipids to generate arachidonic acid.
Arachidonic acid then forms the substrate for cyclooxygenase- and
lipoxygenase (LOX)-dependent synthesis of the four major classes of
eicosanoids: prostaglandins, prostacyclins, thromboxanes, and leukotrienes. These synthetic pathways involve a series of oxidation steps that involve a number of free radical intermediates
(78). Arachidonic acid metabolism, particularly involving
the LOX pathway, which leads to leukotriene synthesis, has been
reported to generate ROS (30, 170, 207, 272). LOX activity
has also been implicated in redox-regulated signaling by ANG II
(306), epidermal growth factor (EGF) (196),
and IL-1 (36). There is the suggestion that LOX-derived
lipid peroxidation products may be involved in the oxidative stress
response to asbestos (74). TNF--induced apoptosis
appears to be mediated by a LOX-dependent but ROS-independent mechanism
(213). A lipid-metabolizing enzyme in fibroblasts similar to 15-LOX has been shown to generate large amounts of extracellular O2
· that appears to be independent of flavoenzyme
activity (212).
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MEASUREMENT OF ROS IN BIOLOGICAL SYSTEMS |
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The high reactivity and relative instability of ROS make them extremely difficult to detect or measure in biological systems. Thus assessments of ROS and free radical generation have largely been made by indirect measurement of various end products resulting from the interaction of ROS with cellular components such as lipids, protein, or DNA (78, 231). Most methods for identification of specific ROS are based on reactions with various "detector" molecules that are oxidatively modified to elicit luminescent or fluorescent signals. Although detailed descriptions of these methods are beyond the scope of this review, we briefly discuss the limitations of the more commonly used assays.
Lucigenin has been used extensively as a chemiluminescent substrate for
the detection of O2· in many biological systems
(97, 101, 121, 168, 235, 274). This is based on the
ability of lucigenin (Luc2+) to be reduced to
LucH·+, which can then react with O2
·
to yield an unstable dioxetane compound that yields light (emission of
photons) in the process of spontaneously decomposing to its ground-state electronic configuration (73). It has
recently been demonstrated (171) that several enzymatic
systems in vitro are capable of univalently reducing Luc2+
even in the absence of O2
· generation, resulting in
the formation of LucH·+ that can autooxidize to generate
O2
·. The ability of lucigenin to "redox cycle"
in this manner, much like the effects of paraquat and nitro blue
tetrazolium, is thought to be a major limitation in the use of
this compound in the detection of O2
·
(171). However, the importance of this redox cycling
effect of lucigenin when applied to biological systems has been
questioned by other investigators (6, 168, 274). The use
of an alternative chemiluminescent probe, coelenterazine, may present
less of a concern with regard to the potential redox-cycling effects of these compounds (287).
Another technique that is widely used for the detection of intracellular H2O2 production in response to growth factor stimulation is based on oxidation of the nonfluorescent substrate 2',7'-dichlorofluorescin (DCFH) to the fluorescent product 2',7'-dichlorofluorescein (DCF) (24, 196, 280). The esterified form of DCFH, dichlorofluorescin diacetate (DCFH-DA), is able to cross cell membranes and then, as a result of deacetylation by intracellular esterases, forms DCFH, which becomes "trapped" intracellularly. This property allows for assessment of intracellular oxidant production. It is becoming increasingly clear, however, that this assay lacks specificity and may be a better indicator of overall changes in the intracellular redox state of the cell than a direct measure of intracellular H2O2 production (122, 247). Recent work (244, 245) also suggests that similar to the problem with lucigenin, a series of free radical chain reactions with DCFH in the presence of peroxidase (and even in the absence of H2O2) may give rise to "artificial" DCF-dependent fluorescence and O2 consumption.
Assessments of extracellular ROS production appear to be relatively
more reliable and may allow for quantitative measurements. The method
for detection of O2· release with the method of
SOD-inhibitable reduction of ferricytochrome c, initially
described for neutrophils by Babior et al. (21), has been
successfully used in other cell systems (187, 268). However, this method, although quite specific for
O2
·, lacks sensitivity and may underestimate net
O2
· production due to the potential reoxidation of
ferricytochrome c by other oxidants (16).
Cellular production of extracellular H2O2
release can be measured by a fluorometric method that is based on the
ability of heme peroxidases to catalyze
H2O2-dependent dimerization of substituted phenolic compounds (221, 248). The major advantages of
this method are its high specificity and sensitivity for
H2O2 as determined with the use of horseradish
peroxidase (used in most assays). The high sensitivity of such assays
is related, at least in part, to the high reactivity of horseradish
peroxidase (severalfold higher than catalase) with
H2O2 (221). We (293)
have been able to detect absolute concentrations of
H2O2 in the 108 M range and a
steady-state release of extracellular H2O2 of
~22 pmol · min
1 · 106
cells
1 from TGF-
1-treated fibroblasts in cell culture
using this method. Because the fluorescence of the dimerized product is
dependent on pH, careful consideration must be made for possible pH
changes and overoxidation of the substrate (221).
The only analytic method that, at least theoretically, measures free radicals directly is electron spin resonance spectroscopy. However, it is relatively insensitive and requires steady-state concentrations in the micromolar range for detection and is, therefore, of limited value in most biological systems. This problem may be circumvented by the technique of spin trapping, which involves the addition of a "spin trap" (usually a nitrone or a nitroso compound) that reacts rapidly with free radicals to form more stable radical adducts that accumulate to concentrations in the detectable range (115, 240). Thus all of the currently available methods for the detection of ROS or free radicals in biological systems, including electron spin resonance spectroscopy, are, by definition, indirect (because detector compounds are required) and semiquantitative (because specific ROS are in competition with other biomolecules that can react with these detector molecules). However, if the redox chemistries of the various detector molecules are carefully considered and the potential limitations of these assays are understood, they can provide useful information on the production and regulation of ROS in biological systems.
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LIGAND-INDUCED ROS PRODUCTION IN NONPHAGOCYTIC CELLS |
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A variety of cytokines and growth factors that bind
receptors of different classes have been reported to generate ROS in
nonphagocytic cells (Table 1). Currently
available information on the enzymatic source(s) and physiological
actions of ROS generated by these ligand-receptor interactions are
summarized here (see Fig. 1 for 3 such
pathways).
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Cytokine receptors.
Cytokine receptors fall into a large and heterogeneous group of
receptors that lack intrinsic kinase activity and are not directly
linked to ion channels or G proteins. Cytokines such as TNF-, IL-1,
and interferon (IFN)-
were among the first reported to generate ROS
in nonphagocytic cells (187, 190, 191). There is no
consensus on the specific species produced, the enzymatic source, or
the site of generation of ROS for these cytokines. In the case of
TNF-
, recent reports (49, 169, 257, 270, 319) suggest
that a mitochondrial source of ROS is required for activation of the
transcription factor nuclear factor (NF)-
B and NF-
B-dependent
gene transcription. There is also the suggestion that TNF-
may
activate NF-
B by an ROS-independent mechanism and that TNF-
and
oxidants may produce a synergistic effect in this activation
(126). TNF-
-induced generation of mitochondrial ROS has
been implicated in apoptotic cell death (269).
Overexpression of Mn SOD inhibits TNF-
-induced apoptosis, supporting
a role for mitochondrial O2
· production in
mediating this effect (181). The mechanism of TNF-
-induced apoptosis appears to be related, at least partially, to
depletion of GSH, leading to redox-dependent formation of ceramide from
sphingomyelin (172, 273). Gotoh and Cooper
(94) showed that TNF-
activates apoptosis
signal-regulating kinase-1 (ASK-1), a member of the MAPK kinase kinase
superfamily, by inducing oxidant-dependent dimerization of ASK-1. The
resistance to apoptosis in some cancer cells may be related to the
constitutive activation of NF-
B by autocrine production of TNF-
(86). ROS-dependent mechanisms also appear to be involved
in TNF-
-induced expression of cell adhesion molecules (12,
147, 233, 318), IL-8 expression (147, 266),
production of chemokines (27, 62), and induction of cardiac myocyte hypertrophy (206).
RTKs.
A number of growth factors that bind RTKs have been shown to generate
intracellular ROS essential for mitogenic signaling. A decade ago, PDGF
was shown to stimulate cellular production of
H2O2, which was thought to function as a
"competence factor" in BALB/3T3 cell growth (264).
Sundaresan et al. (280) demonstrated the ability of PDGF
to transiently increase intracellular concentrations of
H2O2, which was required for PDGF-induced
tyrosine phosphorylation, MAPK activation, DNA synthesis, and
chemotaxis. PDGF also activates the signal transducer and activator of
transcription (STAT) family of transcription factors by a
H2O2-dependent mechanism (271). Interestingly, H2O2 appears to antagonize the
PDGF effect on disruption of gap junction communication by abrogating
the phosphorylation of a gap junctional protein, connexin 43, by a
tyrosine kinase- and redox-dependent mechanism (116). PDGF
has also been shown to regulate gene expression by
O2·-dependent pathways. PDGF stimulates
flavoenzyme-dependent O2
· generation in human
aortic smooth muscle cells by PKC- and wortmannin-sensitive pathways
(184). In this study, PDGF-induced O2
·
production appears to participate in vascular lesion formation by
activating NF-
B and inducing monocyte chemoattractant protein-1 expression. PDGF-induced O2
· (but not
H2O2) appears to be involved in its
upregulation of inducible NOS- and NO·-dependent release of
PGE2 in fibroblasts (134).
Receptor serine/threonine kinases.
All receptor serine/threonine kinases described to date in mammalian
cells are members of the TGF- superfamily. TGF-
1 is the prototype
of this large family of polypeptide growth factors that bind receptor
serine/threonine kinases and include the TGF-
s, activins, inhibins,
bone morphogenetic proteins, and Mullerian-inhibiting substance
(185, 227). Each member of the TGF-
superfamily
activates a heteromeric complex of type I-type II receptors in a
combinatorial manner, leading to the phosphorylation and/or activation
of the recently described SMAD proteins that translocate to the nucleus to mediate gene transcription (185). Unlike RTK(s)-linked
growth factors, TGF-
1 typically inhibits growth of most target
cells. Proliferative responses to TGF-
1 appear to be primarily
related to the indirect effects on the autocrine production of
mitogenic growth factors (29, 164) or their receptors
(241, 291). These multifunctional effects of TGF-
on
cellular growth regulation as well its diverse effects on cell
differentiation and extracellular matrix production are critical in
complex biological processes such as embryogenesis, fibrosis, and carcinogenesis.
G protein-coupled receptors. G protein-coupled receptors are the largest family of cell surface receptors, with >100 members characterized in mammals (9, 239). A number of ligands that bind to these receptors have been shown to generate ROS in different cell systems. Examples of these ligands include ANG II, serotonin [5-hydroxytryptamine (5-HT)], bradykinin, thrombin, and endothelin (ET).
ANG II is a vasoactive peptide that in addition to its effect on vasomotor tone, has proliferative and hypertrophic effects on vascular smooth muscle. ANG II has been shown to stimulate ROS production in cultured vascular smooth muscle cells (97, 297), glomerular mesangial cells (125), endothelial cells (288) and renal proximal tubular cells (104). Griendling et al. and Zafari et al. demonstrated that ANG II activates both NADH- and NADPH-dependent O2Ion channel-linked receptors.
Ion channel-linked receptors mediate rapid synaptic signaling between
electrically excitable cells by transiently opening and closing an ion
channel formed by the ligand-bound receptor complex. Such ligands
typically are neurotransmitters (e.g., acetylcholine, 5-HT, glutamate,
glycine, and -aminobutyric acid). Compared with the other classes of
receptors discussed above, relatively little is known about ROS
signaling by ion channel-linked receptors. However, there is growing
interest in the role of ROS in mediating neuronal cell death by some
excitatory neurotransmitters. Glutamate induces ROS production in
neuronal cells by mechanisms that have been shown to be both dependent
and independent of the changes in intracellular ion concentrations
(35, 260). Work by Sensi and colleagues (260,
261) suggests that ROS generation in these cells is a result of
intracellular Zn2+-mediated mitochondrial depolarization.
Acetylcholine has been shown to activate ATP-sensitive K+
channels and increase mitochondrial ROS that may function as an
intracellular signal for acetylcholine-induced preconditioning in
cardiomyocytes (317).
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SIGNALING MOLECULES "TARGETED" BY ROS |
---|
Although a large number of signaling pathways appear to be regulated by ROS, the signaling molecules targeted by ROS are less clear. There is growing evidence, however, that redox regulation might occur at multiple levels in the signaling pathways from receptor to nucleus.
Receptor kinases and phosphatases themselves may be targets of
oxidative stress. Growth factor receptors are most commonly activated
by ligand-induced dimerization or oligomerization that autophosphorylates its cytoplasmic kinase domain (107).
Ligand-independent clustering and activation of receptors in response
to ultraviolet light have also been well demonstrated (243,
249), and this effect appears to be mediated by ROS (118,
226). Exogenous H2O2 (usually in the
millimolar range) has been shown to induce tyrosine phosphorylation and
activation of the PDGF-, PDGF-
, and EGF receptors (82, 87,
91). Lysophatidic acid-induced activation of the EGF receptor
appears to be mediated by the intermediate formation of ROS
(57). A study by Knebel et al. (138) suggests that the mechanism of these effects may be related to ROS-mediated inhibition of the dephosphorylation of RTKs by inactivation of membrane-bound protein tyrosine phosphatase(s). A similar action of
either O2
·- or NO·-generating stimuli on the
phosphorylation-dephosphorylation balance leading to PDGF receptor
activation has also been reported (41). However, to our
knowledge, no studies have demonstrated the ability of endogenous,
growth factor-stimulated ROS to regulate its own (or other) receptor(s)
activation. On the other hand, H2O2 production
in response to EGF has been shown to require a functional EGF receptor
kinase domain (24), suggesting that growth factor-induced
ROS may function downstream from EGF receptor activation. This does not
exclude the possibility that, under certain pathological conditions
associated with oxidative stress, ROS may directly activate cell
surface receptors.
Because most growth factors and cytokines appear to generate ROS at or near the plasma membrane, phospholipid metabolites are potentially important targets for redox signaling. Takekoshi et al. (286) showed that the oxidized forms of diacylglycerol were more effective in activating PKC than its nonoxidized forms. PKC activation and protein tyrosine phosphorylation appear to be required for H2O2-induced PLD activation in endothelial cells and fibroblasts (197, 209). This effect may be mediated by the upstream activation of growth factor receptors because suramin (an inhibitor of receptor activation) blocks H2O2-induced PLD activation (208). EGF signaling of PLA2 activation and arachidonic acid release is sensitive to antioxidants suggesting that PLA2 may be a target of ROS (88).
Non-RTKs belonging to the Src family (Src kinases) and Janus kinase (JAK) family have been reported to be regulated by various forms of oxidative stress (2, 7, 271). As in the case of RTKs, these reports relate primarily to the effects of exogenously added oxidants, and the significance of such actions in specific growth factor- or cytokine-mediated signaling is less clear. Simon et al. (271) have demonstrated, however, that PDGF-induced activation of the JAK-STAT pathway is redox sensitive, suggesting a role for endogenous oxidant production in mediating this effect. Src kinases and JAKs appear to be involved in H2O2-induced activation of p21Ras in fibroblasts (2). In another study, Lander et al. (150) have shown that p21Ras may be a common signaling target of NO· and ROS. This effect may involve the recruitment of phosphatidylinositol 3'-kinase to the plasma membrane where it associates directly with the effector domain of p21Ras before being activated (64).
ROS signaling by the induction of changes in intracellular
Ca2+ ([Ca2+]i) has been studied
in a number of cell types including smooth muscle cells (reviewed in
Ref. 285). Roveri et al. (246) showed that
H2O2 induces a rapid increase in
[Ca2+]i that appears to be related to
inositol 1,4,5-triphosphate-sensitive Ca2+ stores in the
sarcoplasmic reticulum (SR) followed by a slower increase in
[Ca2+]i that is most likely derived from the
extracellular space (246). Both O2·
(98, 283, 284) and H2O2
(99) have been shown to inhibit the activity of
ATP-dependent Ca2+ of the SR, which would result in passive
diffusion of SR Ca2+ into the cytosol. Such effects may
also be more important in oxidative stress responses (179)
than in receptor-mediated signaling by growth factors and/or cytokines.
The MAPKs comprise a large family of PKs that include ERK1 (p44MAPK)/ERK2 (p42MAPK), JNKs (also known as the stress-activated PKs), and p38 MAPKs. Because the MAPK pathways mediate both mitogen- and stress-activated signals, there has been significant interest in the redox regulation of these pathways. A number of groups (4, 23, 100, 195, 201, 277) have demonstrated the ability of exogenous oxidants to activate the ERK MAPK pathway. The mechanism(s) for this effect is unclear, and the precise molecular target(s) is unknown. Some studies suggest that ROS-mediated ERK activation may be an upstream event at the level of growth factor receptors (100), Src kinases (7), and/or p21Ras (201). Another potential mechanism for this effect may be oxidant-induced inactivation of protein tyrosine phosphatases (PTPs) and/or protein phosphatase A (307). There are relatively fewer reports of endogenous ROS regulating the ERK MAPK pathway. However, Wilmer et al. (310) showed that IL-1-induced activation of ERK2 and JNK in human mesangial cells was inhibited by antioxidants, suggesting that ligand-stimulated ROS may be involved in mediating this effect. Also, serum- and 12-O-tetradecanoylphorbol-13-acetate-induced p21 induction appears to be mediated by redox-regulated ERK activation in HeLa cells (70). Results from our laboratory (159) suggest that redox regulation of the ERK pathway may be ligand and cell specific. 5-HT-induced ERK1/ERK2 activation in smooth muscle cells is redox sensitive, whereas FGF-2-stimulated activation of ERK1/ERK2 in lung fibroblasts is not (Thannickal et al., unpublished observations). Recent work also suggests that cyclin D1 expression, independent of the ERK MAPK pathway, may be a downstream target of redox-regulated mitogenic signaling (218). In vascular endothelial cells, cyclic strain-induced ROS can modulate egr-1 expression, at least partially, via the ERK signaling pathway (314).
Other members of the MAPK family have also been implicated as potential
targets of ROS. Big MAPK-1 (BMK-1) appears to be much more sensitive
than ERK1/ERK2 to H2O2 in several cell lines
tested and suggests a potentially important role for BMK-1 as a
redox-sensitive kinase (3). A study by Lo et al.
(177) suggests that TNF-- and IL-1-induced activation
of JNK may be mediated by intracellular H2O2.
ANG II (306) and EGF (17) have also been
reported to have similar effects. Generation of ROS in response to
hypoxia-reoxygenation and ischemia-reperfusion mediates JNK activation
in cardiac myocytes (144) and perfused rat heart
(54). Although not directly related to the MAPK family,
p66shc, a splice variant of the p52shc/p46shc protein involved in
mitogenic signaling from activated receptors to p21Ras, was
found to be a target of H2O2 and responsible
for mediating stress apoptotic responses (194).
NF-B, a transcription factor that regulates the expression of a
number of genes involved in immune and inflammatory responses, has long
been considered oxidant responsive (193, 256). Significant progress has been made on the mechanisms of activation of this transcription factor, and the regulation of upstream I
B kinases that
phosphorylate I
B, a critical step in NF-
B activation, has been
recently characterized (130). However, the mechanism(s) by
which ROS regulate this activity has remained elusive. Recent reviews
(38, 167) on this subject have emphasized the importance of the recognition that a redox-dependent activation of NF-
B is cell
and stimulus specific as opposed to the concept that oxidative stress
is a common mediator of diverse NF-
B activators. Li and Karin
(167) found that when a redox-regulated effect is
observed, it appears to occur downstream from the I
B kinases, at the
level of ubiquitination and/or degradation of I
B.
Activator protein-1 (AP-1), a transcriptional complex formed by the
dimerization of Fos-Jun or Jun-Jun proteins, has also been demonstrated
to be regulated by redox mechanisms. Both exogenous oxidants (11,
211) and ligand-induced ROS (176, 232) have been
implicated in AP-1 activation. Unlike NF-B, however, AP-1 appears
also to be activated by some antioxidants (52, 321). In
vitro experiments suggest that a single cysteine residue in the highly
conserved tri-amino acid sequence Lys-Cys-Arg of the DNA binding domain
of Fos and Jun proteins confers redox sensitivity to AP-1
(1). It was suggested from this study that this single cysteine residue was unlikely to account for the formation of inter- or
intramolecular disulfide bonds but rather for the possible conversion
of this cysteine to a reversible oxidation product such as sulfenic
acid. Further evidence suggests that the redox regulation of AP-1 DNA
binding is facilitated by the reducing activity of redox factor-1
(Ref-1) protein that may act directly on this critical cysteine residue
(315). Other transcription factors in which DNA binding is
regulated by similar redox mechanisms include Sp-1 (313),
c-Myb (203), p53 (234) and egr-1
(117).
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MECHANISMS OF ROS ACTION |
---|
Current concepts of ROS signaling can be divided into two general mechanisms of action: 1) alterations in intracellular redox state and 2) oxidative modifications of proteins.
Alterations in intracellular redox state.
In comparison with the extracellular environment, the cytosol is
normally maintained under strong "reducing" conditions. This is
accomplished by the "redox-buffering" capacity of intracellular thiols, primarily GSH and thioredoxin (TRX). The high ratios of reduced
to oxidized GSH and TRX are maintained by the activity of GSH reductase
and TRX reductase, respectively. Both of these thiol redox systems
counteract intracellular oxidative stress by reducing both
H2O2 and lipid peroxides, reactions that are catalyzed by peroxidases (e.g., GSH peroxidase catalyzes the reaction H2O2 + 2GSH 2H2O + GSSG). Accumulating evidence suggests that, in addition to their
"antioxidant" functions, GSH and TRX participate in cell signaling processes.
Oxidative modifications of proteins.
ROS can alter protein structure and function by modifying critical
amino acid residues, inducing protein dimerization, and interacting
with Fe-S moieties or other metal complexes (see Fig. 2). Oxidative modifications of critical
amino acids within the functional domain of proteins may occur in
several ways. By far, the best described of such modifications involves
cysteine residues. The sulfhydryl group (-SH) of a single cysteine
residue may be oxidized to form sulfenic (-SOH), sulfinic
(-SO2H), sulfonic (-SO3H), or
S-glutathionylated (-SSG) derivatives (Fig. 2A). Such
alterations may alter the activity of an enzyme if the critical
cysteine is located within its catalytic domain (28) or
the ability of a transcription factor to bind DNA if it is located
within its DNA-binding motif (1). PTP-1B is directly
inactivated by ROS-induced reversible oxidation of its catalytic site,
Cys215, and this has been proposed as a mechanism for
EGF-mediated mitogenic signaling (28, 163). Recent work by
Barrett et al. (28) suggests that although both
O2· and H2O2 are capable of
inactivating PTP-1B, O2
· may be the more relevant
species due to its higher specificity, activity, and reversibility.
This study also suggested that the specific cysteine modification
involves S-glutathionylation, which is readily reversed to the active
sulfhydryl group by thioltransferases. Reversible S-glutathionylation
also appears to form the basis for redox regulation of c-Jun DNA
binding (137). Schmid et al. (255) recently
described a novel mechanism for "redox priming" based on the
ability of phosphocreatine in combination with
H2O2 to serve as an alternate phosphate donor
for the autophosphorylation of the insulin receptor kinase. In this
study, the priming effect of H2O2 appears to
involve conversion of four cysteine residues into sulfenic acid, which
produces a structural change in insulin receptor kinase that allows for
phosphocreatine binding at a site distinct from that of ATP.
|
![]() |
CONCLUSION |
---|
The concept that ROS have "purposeful" roles as "regulators" of cell function or as "signaling molecules" has gained significant recognition over the past several years from studies done in laboratories worldwide. The evidence supporting this concept is based largely on the following criteria: 1) growth factors and cytokines are capable of generating ROS in a number of different cell types, 2) antioxidants and inhibitors of ROS-generating enzymatic systems block specific growth factor- and/or cytokine-activated signaling events or physiological effects, and 3) exogenous addition of oxidants activates the same cytokine- and/or growth factor-mediated signaling pathway or produces the same physiological effects. However, investigators must recognize potential technical drawbacks when applying these criteria to establish cause-effect relationships between ROS and cell signaling/regulation. First, the measurement of ROS in biological systems can be misinterpreted if the redox chemistries of the detector molecules used in these assays are not carefully considered. Secondly, antioxidants and enzymatic inhibitors have multiple potential targets, and their effects may be due to nonspecific actions rather than their "intended" actions to degrade or scavenge ROS and inhibit ROS-generating enzymes, respectively. Finally, exogenous addition of oxidants as a "bolus" and/or in relatively high concentrations does not simulate the conditions of tightly regulated and "compartmentalized" ROS production in response to physiological ligands.
The identity of the specific oxidase(s) activated by growth factors
and/or cytokines in nonphagocytic cells is still in need of
clarification. Although there are numerous reports of the expression of
protein subunits of the multicomponent phagocytic NADPH oxidase in such
cells, it is not known if assembly or activation of the same or a
similar enzymatic complex is responsible for ligand-stimulated ROS
production. Recent cloning and characterization of the homologues of
the phagocytic NADPH oxidase, the Nox (formerly Mox) family of oxidases
(279), may lead to improved understanding of oxidases in
cell signaling. Although PDGF has been shown to increase mRNA expression of Nox-1 in vascular smooth muscle cells (279),
its role in the "early and immediate" generation of ROS after
ligand binding is still unclear. A study by Thannickal et al.
(291) on the ROS-generating effects of various ligands in
lung fibroblasts suggest that the enzymatic sources and their
regulation by mitogenic growth factors versus TGF-1 are distinctly
different. Taken together, it appears that a family of
NAD(P)H-dependent oxidoreductases in nonphagocytic cells functions as
generators of "redox signals" at the plasma membrane in response to
growth factor and/or cytokine stimulation.
A major gap in our understanding of ROS signaling is the mechanism(s)
by which these molecules transduce their cellular signals. The emerging
evidence for the oxidative modification of proteins by ROS provides one
of the more plausible mechanisms for such signaling. However, several
questions remain. How is the specificity of action achieved? How are
ROS "disposed" of after they have mediated their action? What is
the mechanism for the "reversibility" of action or the cyclical
"on-off" switch that would be expected (much
like phosphorylation-dephosphosphorylation)? Recent
work has begun to shed light on some of these questions.
Barrett et al. (28) postulated that the specificity of
O2· (over the neutral H2O2)
for PTP-1B inactivation may be related to the presence of positively
charged residues surrounding the site of action. Similarly, the extreme
sensitivity of OxyR to low concentrations of
H2O2 appears to be related to conserved amino
acid residues surrounding the two active-site cysteines (325). In addition, the site of ROS production
(compartmentalization), the specific reactive species
(O2
· versus H2O2) produced,
and the concentration and kinetics of ROS generation are all likely to
be important factors in determining the physiological actions and
effects of ROS in cell signaling.
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ACKNOWLEDGEMENTS |
---|
This work was supported by National Heart, Lung, and Blood Institute Grants K08-HL-03552 (to V. J. Thannickal) and HL-42376 (to B. L. Fanburg).
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FOOTNOTES |
---|
Address for reprint requests and other correspondence: V. J. Thannickal, Pulmonary and Critical Care Division, New England Medical Center, 750 Washington St., NEMC #257, Boston, MA 02111 (E-mail: vthannickal{at}lifespan.org).
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