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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 92, Num. s2, 1997, pp. 115-123
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Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 92, Suppl. II, pp. 115-123
Signal Transduction and Activation of the NADPH Oxidase in Eosinophils
Mark A Lindsay^+, Mark A Giembycz
Thoracic Medicine, Imperial College School of Medicine, National Heart and
Lung Institute, Dovehouse Street, London SW3 6LY, UK
^+Corresponding author. Fax: +44-171-351. 5675. E-mail: m.lindsay@ic.ac.uk
Received 3 September 1997; Accepted 30 September 1997
Code Number:OC97176
Sizes of Files:
Text: 45.4K
Graphics: Line drawings and photographs (jpg) - 137.6K
Activation of the eosinophil NADPH oxidase and the subsequent release of
toxic oxygen radicals has been implicated in the mechanism of parasite
killing and inflammation. At present, little is known of the signal
transduction pathway that govern agonist-induced activation of the
respiratory burst and is the subject of this review. In particular, we
focus on the ability of leukotrine B4 to activate the NADPH oxidase in
guinea-pig peritoneal eosinophils which can be obtained in sufficient
number and purity for detailed biochemical experiments to be performed.
Key words: leukotriene B4 - eosinophil - NADPH oxidase - signal
transduction
The NADPH oxidase (E.C. 1.23.45.3) catalyses the single electron reduction
of molecular O2 to superoxide (O2^- ), a powerful oxidising and reducing
agent (Fig. 1) (Babior et
al. 1973). In the presence of superoxide dismutase, O2^- dismutates to
hydrogen peroxide (H2O2) which can be subsequently converted into
hypobromous acid in the presence of eosinophil peroxidase (a highly basic
protein stored within specific eosinophil granules) and bromide (Weiss et
al. 1986) (Fig. 1). Alternatively, in the presence of ferrous ions, O2^-
and H2O2 interact to form the membrane-perturbing hydroxyl radical (OH^.),
one of the most unstable oxidising species known (Fig. 1). Other pathways
of free radical formation have also been described including the reaction
of O2^- with nitric oxide to form peroxynitrite which provides an
additional, iron-independent route of OH^. formation together with nitrogen
dioxide radicals (Fig. 1). Hypobromous acid is able to interact with H2O2
to form singlet oxygen, the biological significance of which is currently
unclear (Fig. 1). Activation of the NADPH oxidase and the subsequent
production of toxic oxygen radicals is thought to be important to the role
of eosinophils during host defence (Butterworth & Thorne 1993). However, it
is now appreciated that NADPH oxidase activation maybe cytotoxic to many
mammalian cells, particular those of the gut, skin and lung, a finding that
has implicated eosinophils in the pathogenesis of a number of non-parasitic
inflammatory disorders, including Crohn's disease, atopic dermatitis and
allergic asthma (Butterfield & Leiferman 1993). Indeed, the activity of the
NADPH oxidase is significantly higher in eosinophils that in other
phagocytes (Yamashita et al. 1985, Petreccia et al. 1987,
Sedgwick et al. 1988, Yagisawa et al. 1996).
Figure 1: generation
of reactive oxygen species in
eosinophils.
At present, little is known of the intracellular mechanisms responsible for
NADPH oxidase activation in eosinophils. This is in contrast to
neutrophils, where studies of the mechanism of O2^- release by the
chemotactic peptide, formyl-methyl-leucyl-phenylalanine (fMLP) have
suggested the participation of phospholipase A2- (PLA2), phospholipase C-
(PLC), phospholipase D- (PLD) protein kinase C- (PKC), phosphatidylinositol
3-kinnase- (PI-3K) and tyrosine kinase-dependent pathways (possibly those
leading to mitogen activated protein kinase stimulation) (Bokoch 1995).
This lack of knowledge relates primarily to the difficulty in obtaining
sufficient numbers of cells, particular human eosinophils. Thus, we and
others have overcome this problem by using guinea-pig eosinophils as a
model system, which can be harvested from the peritoneum in sufficient
numbers for detailed biochemical studies.
Human and guinea-pig eosinophils undergo a rapid and transient activation
of the NADPH oxidase to a range of physiological soluble and particulate
stimuli including leukotriene B4 (LTB4) (Palmbald et al. 1984,
Maghni et al. 1991, Rabe et al. 1992, Subramanian et al.
1992, Perkins et al. 1995), platelet activating factor (PAF)
(Shute et al. 1990, Wymann et al. 1995), fMLP (Palmblad et
al. 1984, Kroegal et al. 1990, Wymann et al. 1995),
complement factor 5a (C5a)(Wymann et al. 1995), interleukin-8 (IL-8)
(Wymann et al. 1995), eotaxin (Elsner et al. 1996, Tenscher
et al. 1996) and opsonized particles (Koenderman et al. 1990,
Shute et al. 1990). Furthermore, pre-incubation with sub-threshold
concentrations of PAF has been demonstrated to prime the subsequent NADPH
oxidase response to opsonized particles (Tool et al. 1992) and fMLP
(Zoratti et al. 1992). More recent studies have demonstrated a
similar priming in human eosinophils adherent to tissue culture plates
coated with a range of extracellular matrix proteins (e.g. fibronectin,
fibrinogen, collagen, laminin) and fetal calf serum. Under these
conditions, the cytokines tumor necrosis factor-a (TNF-a), granulocyte
macrophage-colony stimulating factor (GM-CSF), which are unable to
stimulate the NADPH oxidase in `non-adherent' cells, produce a slowly
developing and sustained generation of O2^- (Dri et al. 1991, Horie
& Kita 1994). However, since there are no studies concerning the
biochemical mechanism of NADPH oxidase activation in adherent eosinophils,
this review will focus predominately upon those studies on `non-adherent'
cells. In particular, we will concentrated upon recent studies of the
mechanism of LTB4-induced NADPH oxidase activation in guinea-pig
eosinophils (Perkins et al. 1995, Lindsay et al. 1995a, b).
Structure and Assembly of the NADPH Oxidase
In neutrophils, an active NADPH oxidase complex assembles at the phagocytic
and plasma membranes following activation (Segal & Abo 1993) (Fig.
2). At least five proteins are required for the formation of an active
oxidase complex: the membrane-bound cytochrome b558 (consisting of two
subunits, gp91^phox and p22^phox ) and the cytosolic
proteins, p47^phox, p67^phox and a small GTP-binding protein,
Rac-1 or Rac2 (Casimer & Teahan 1994, Bokoch 1994). Recently, two
additional components have been identified, these being the cytosolic
protein, p40^phox, that appears to be associated with p67^phox
(Wientjes et al. 1993, Tsunawaki et al. 1994) and the membrane
associated small GTP-binding protein, Rap1a (Gabig et al. 1995). Under
resting conditions, the cytosolic components exist as a 240-300 kDa
oligomer (Park et al. 1992, 1994). Following activation,
translocation of these components to the membrane-bound cytochrome b558 and
assembly of the active oxidase complex is thought to be mediated by a
mechanism involving both protein binding through Src homology 3 (SH3)
domains and phosphorylation of p47^phox (Rosrosan & Leto,
1990, McPhail 1994, Park & Ahn, 1995, Demendez et al. 1996).
Figure 2: structure
of the NADPH oxidase. PPP: proline
rich regions; SH3: src homology domain 3.
In eosinophils, evidence for a similar if not identical mechanism of
oxidase assembly and activation is also available. Thus, the cytosolic
components, p47^phox, p67^phox, p40^phox and membrane
components, p22^phox and gp91^phox have been identified
(Segal et al. 1981, Yagisawa et al. 1996, Zhan et al.
1996) whilst p47^phox and p67^phox have been shown to
reconstitute NADPH oxidase activity in cell free systems prepared from both
neutrophils and eosinophils fractions (Bolsher et al. 1990).
Role of Phospholipase C, Intracellular Ca^2+
and Protein Kinase C
In neutrophils, stimulation of phospholipase C (PLC) is thought to be
central to the activation of the NADPH oxidase. PLC catalyses the
hydrolysis of phosphatidylinositol (4,5)-bisphosphate to inositol
(1,4,5)-trisphosphate (IP3) and diacylglyc-erol (DAG). IP3 can release
Ca^2+ from intracellular stores whilst DAG is known to activate protein
kinase C (PKC). Studies in eosinophils have demonstrated a rapid and
transient increase in both IP3 and [Ca^2+]i following exposure of
guinea-pig and human eosinophils to LTB4, PAF and fMLP (Kroegel et al.
1991, Perkins et al. 1995, Wymann et al. 1995).
Furthermore, human eosinophils release DAG following stimulation with
opsonized particles (Koenderman et al. 1990). However, the
generation of O2-derived free radicals is only marginally suppressed in
Ca^2+-depleted cells, suggesting that neither IP3 nor Ca^2+ play a major
role in the activation of the NADPH oxidase (Subramanian et al.
1992, Perkins et al. 1995, Wymann et al. 1995).
Similarly, whilst the PKC activators, phorbol esters, are potent and robust
stimulants of oxidase activation in guinea-pig and human eosinophils
(Petreccia et al. 1987, Perkins et al. 1995), the PKC
inhibitors Ro-31 8220 (Perkins et al. 1995) and
1-O-hexadecyl-2-O-methylglycerol (Rabe et al. 1992)
only partially inhibit (by 20 to 30%) agonist-induced H2O2 release in
guinea-pig eosinophils, suggesting that PKC is not central to this
response. Indeed, in human eosinophils exposed to opsonised particles, the
rate of oxygen consumption is augmented in the presence of
inhibitors of PKC (van der Bruggen et al. 1993) implying that one of
more of these enzymes can negatively regulate oxidase activation.
Collectively, therefore, these data provide persuasive evidence that
agonist-induced activation of the NADPH oxidase in eosinophils is mediated
by mechanisms that are largely independent of intracellular Ca^2+ and PKC.
Role of Phospholipase D and Phosphatidy-linositol 3-kinase
Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine (PC)
to phosphatidic acid (PA) which can subsequently hydrolysed to
diradylglycerol (DRG) by phosphatidic acid phosphohydrolase. Since PLD is
generally considered to be the predominate pathway for the production of
DAG, it was originally thought that PLD mediates NADPH oxidase activation
following PKC stimulation (Bonser et al. 1989, Thompson et al.
1990, Kessels et al. 1991). However, recent studies in cell free
system have suggested the possible involvement of PA-regulated protein
kinases in the mechanism of p47^phox phosphorylation and NADPH
oxidase activation (McPhail et al. 1995). Attempts to measure PLD
activation in eosinophils have produced conflicting results which is
probably related to differences in the stimuli used. Thus, although C5a
stimulated PLD activation in human eosinophils (Minnicozzi et al.
1990) this was not observed in guinea-pig eosinophils exposed to LTB4
(Perkins et al. 1995). Unusually, the latter study found that
butan-1-ol, an inhibitor of PLD was able to inhibit NADPH oxidase
activation. However, it is likely that the action of butan-1-ol was due to
its ability to elevate intracellular cyclic AMP, which is known to inhibit
the activation of the NADPH oxidase in eosinophils (see below) (Perkins et
al. 1995).
Phosphatidylinositol 3-kinase (PI 3-kinase) catalyses the enzymatic
conversion of phospha-tidylinositol 4,5-bisphosphate to
phospha-tidylinositol 3,4,5-trisphosphate. In neutrophils, this reaction is
apparently pre-requisite for the activation of the NADPH oxidase since
selective inhibitors of PI 3-kinase, such as wortmannin and LY294002,
effectively suppress the generation of O2^- in response to fMLP (Ding et
al. 1995, Vlahos et al. 1995). Furthermore, the use of these
inhibitors has facilitated the identification and characterisation of PI
3-kinase activated protein kinases that are able to phosphorylate peptides
derived from p47^phox (Ding et al. 1995, 1996).
Currently, little is known of the role of PI 3-kinase during activation of
the eosinophil NADPH oxidase. While wortmannin attenuates eotaxin-induced
NADPH oxidase activation in human eosinophils (Elsner et al. 1996),
it has no affect upon LTB4-induced H2O2 generation in guinea-pig
eosinophils at concentrations that abolish the fMLP evoked respiratory
burst in neutrophils (Perkins et al. 1995).
Role of Phospholipase A2 and Arachidonic Acid
It has been proposed that arachidonic acid (AA), cleaved from membrane
phospholipids by PLA2, may play an important role in the activation of the
human neutrophils (Badwey et al. 1984, Curnette et al.
1984, Aebischer et al. 1993, Henderson et al. 1993). The
mechanism underlying these responses is still unknown although AA has been
demonstrated to have a number of intracellular actions in other cell types.
These include the inhibition of ras GTPase activating protein (Homayoun &
Stacey, 1993, Sermon et al. 1996), activation of PKC (Khan et al.
1995) and MAP kinases (Rao et al. 1994, Hii et al. 1995),
increasing intracellular Ca^2+ concentration (Hardy et al. 1995) and
to synergise with GTPgS to cause rac p21 translocation to membrane
fractions and the subsequent activation of the NADPH oxidase in cell-free
systems (Sawai et al. 1993). We have found that addition of
exogenous AA to guinea-pig eosinophils stimulates H2O2 generation in a
concentration-dependent manner (Lindsay et al. 1995a). This response
was unaffected by inhibitors of cyclo-oxygenase and lipoxygenase indicating
that is not mediated by its metabolism to prostaglandins, thromboxane or
leukotrienes and may reflect a direct action of AA. However, the role of
PLA2 activation and the release of AA during receptor mediated NADPH
oxidase activation in eosinophils is virtually unknown. Studies with fMLP-
(White et al. 1993) and opsonized zymosan-stimulated (Shute et
al. 1990) eosinophils have implied a possible role for endogenous
PLA2 in the mechanism of O2^- generation. However, these conclusions were
derived pharmacologically using the non-selective PLA2 inhibitors,
mepacrine and 4-bromophenacyl bromide and did not attempt to measure the AA
release. In recent experiments, using the release of [^3H]AA from
pre-loaded cells as a marker of PLA2 activation, we have investigated the
role of PLA2 during LTB4-induced NADPH oxidase activation. We have found
that the liberation of [^3H]AA from eosinophils occurs with a time- and
concentration-dependence consistent with a causal role in the generation of
H2O2 (Fig. 3). However,
since the non-selective PLA2
inhibitor, mepacrine caused only a small inhibition of H2O2 generation at a
concentration (50mM) that completely attenuated [^3H]AA release, this
suggests that PLA2 activation is not central to the mechanism of
LTB4-induced NADPH oxidase activation (Fig. 3).
Figure 3:
LTB4-induced phospholipase A2 and NADPH
oxidase activation in guinea-pig eosinophils. The time (A,D) and
dose-dependent (B,E) release of [^3H]AA and maximal rate of H2O2 generation
and the affect of the PLA2 inhibitor, mepacrine upon the these two
responses (C,F), was measured in control (-n-) and LTB4-stimulated (1mM)
(-o-) guinea-pig eosinophils. Control H2O2 release was essentially zero.
Role of MAP kinases and Tyrosine kinases
MAP kinases is the generic term used to describe an ever increasing family
of serine/threonine kinases. At present, the three most characterised MAP
kinases families are the extracellular regulated kinases 1 and 2 (ERK1/2),
the c-jun N-terminal kinases 46 and 54 (JNK46/JNK54) and the p38 kinases.
The upstream mechanisms that regulate the activation of the MAP kinases are
presently an area of intense investigation.
The LTB4-, C5a- and fMLP-stimulated responses are thought to activate
eosinophils via intercalation with receptors linked to the pertussis toxin
sensitive G-protein, Gi (Kita et al. 1991, Miyamasu et al.
1995, Wymann et al. 1995, Lindsay et al. 1995b). Recent
studies in both neutrophils and transfected cell lines, have identified
some salient aspects of the mechanism of Gi-linked MAP kinase activation
(for reviews see Bokoch, 1995, 1996, Denhardt 1996). In the case of ERK1/2
activation, the release of the bg subunit of Gi results in the
phosphorylation of Shc and the subsequent engagement of Grb2-Sos by a
mechanism involving phosphatidylinositol 3-kinase (Downey et al.
1996) and the a Src-like tyrosine kinase (Wan et al. 1996). The
guanine nucleotide exchanger, Sos stimulates GDP/GTP exchange and
activation of p21^ras. Activated p21^ras recruits the
serine/threonine kinase Raf-1 to the plasma membrane where it is stimulated
by an as yet unidentified mechanism. Raf-1 then catalyses the
phosphorylation and activation of MAP kinase kinase 1/2 (MEK1/2) which can
subsequently phosphorylate and activate the ERK1/2 MAP kinase. At present,
much less is known of the pathway responsible for Gi-linked activation of
the JNK and p38 MAP kinases. Once again the mechanism is thought to involve
the bg subunit which acts through members of the Rho family of small
GTP-binding proteins (rac1 and cdc42). These GTP-binding proteins are
believed to stimulate PAK, a p21-activated kinase, which in turn
phosphorylates and activates a sequence containing MEK kinases, then MEKs
and finally the JNK and p38 MAP kinases. Since the cytosolic component
p47^phox has been demonstrated to contain possible MAP kinase
phosphorylation sites whilst another cytosolic component, rac1 is involved
in the mechanism of MAP kinase activation, this pathway is potentially
important in the mechanism of NADPH oxidase activation.
Although there are no studies demonstrating NADPH oxidase activation by
interleukin-5 (IL-5), this cytokine has been reported to cause activation
of the lyn-ras-raf1-MEK-ERK pathway in human eosinophils (Pazdrak et al.
1995, Bates et al. 1996). Furthermore, 5-oxo-eicosatetraenoate
(5-oxoETE) has been shown to phosphorylate the p42 and p44 MAP kinase
(probably ERK1/2) in human eosinophils (O'Flaherty et al. 1996) whilst
Araki et al. (1995) have demonstrated PKC-independent activation of raf1
and ERK following LTB4-activation of guinea-pig eosinophils. We have
extended the later study and shown LTB4-induced phosphorylation of the p38
MAP kinases although we were unable to demonstrated activation of JNKs ( Fig. 4). However, since the
selective inhibitors of ERK and p38
MAP kinases, PD098059 (Alessi et al. 1995, Dudley et al.
1995) and SK203580 (Lee et al. 1994) respectively, failed to
significantly attenuate H2O2 generation (Fig. 5), this
suggested that MAP kinases do not mediate LTB4-induced NADPH oxidase
activation.
Figure 4:
LTB4-induced MAP kinase activation in
guinea-pig eosinophils. Time dependent effect of LTB4 stimulation (1mM)
upon ERK1/2 (A) and JNK46/54 (B) activation and p38 MAP kinase
phosphorylation (C) in guinea-pig eosinophils. ERK1/2 and JNK46/54 activity
were measured using an in-gel renaturation assay employing myelin basic
protein and GST-c-jun, respectively, as the substrates whilst p38
phosphorylation was determined by western blotting with an anti-phospho-p38
specific antibody (p38-P).
Figure 5: effect of
MAP kinase inhibitors upon
LTB4-induced NADPH oxidase activation in guinea-pig eosinophils.
Eosinophils were pre-incubated for 10 min and 30 min with PD098059 (A) and
SB203580 (B), respectively, stimulated with 1mM LTB4 and the maximum rate
of H2O2 generation determined. Control H2O2 release was essentially zero.
A number of inhibitor studies have implicated a possible role for protein
tyrosine kinases during NADPH oxidase activation in eosinophils (Nagata et
al. 1995, Elsner et al. 1996). Since these inhibitors may
exert their action through inhibition of the src-related tyrosine kinases,
their affects maybe secondary to inhibition of the MAP kinases cascade.
However, our observation that the tyrosine kinase inhibitors, herbimycin A
and lavendustin A, can dose dependently inhibit the MAP kinase-independent
LTB4 response in guinea-pig eosinophil (Fig. 6), suggests the
existence of an additional tyrosine kinase dependent pathway(s) responsible
for NADPH oxidase activation.
Figure 6: Effect of
tyrosine kinase inhibitors upon
LTB4-induced NADPH oxidase activation in guinea-pig eosinophils.
Eosinophils were pre-incubated for 5min with the stated concentration of
lavendustin A and herbimycin A. Following 1mM LTB4 stimulated, the maximal
rate of H2O2 generation was determined. Control H2O2 release was
essentially zero.
Inhibition of the NADPH Oxidase by Cyclic AMP
A number of cyclic AMP-elevating drugs inhibit agonist-induced activation
of the NADPH oxidase in eosinophils. Pre-treatment of eosinophils with
b2-adrenoceptor agonists such as salbutamol, partially suppress this
response but short periods of pre-incubation are necessary if inhibition is
to be seen (Yukawa et al. 1990, Rabe et al. 1993). This
phenomenon is believed to be due to the rapid development of tachyphylaxis,
and may be due to uncoupling of b-adrenoceptors since receptor
down-regulation is not observed. Paradoxically, the long-acting b2-agonists
salmeterol is inactive on guinea-pig eosinophils and actually behaves as a
competitive antagonist. However, this might relate to the very poor
efficacy of salmeterol coupling, with a low density of b-adrenoceptors on
eosinophils.
Lipophilic cyclic AMP analogues (Dent et al. 1991) and selective
inhibitors of the phosphodiesterase (PDE) 4 isoenzymes family also
effectively prevent activation of the respiratory burst oxidase (Dent et
al. 1991, 1994, Souness et al. 1991, Barnette et al.
1995, Hatzelmann et al. 1995).
Conclusion
In comparison to neutrophils, little is known of the mechanism of NADPH
oxidase activation in eosinophils. As a consequence of the difficulties in
obtaining sufficient numbers of cells for biochemical studies, the majority
of the detailed biochemical studies have been performed using guinea-pig
peritoneal eosinophils. However, where detailed studies have been
performed, these results suggest there maybe fundamental difference between
the mechanism of NADPH oxidase in eosinophils and neutrophils. Thus,
increases in intracellular Ca^2+ concentration and protein kinase C
activation are not required for NADPH oxidase activation in either human or
guinea-pig eosinophils. Furthermore, in contrast to fMLP stimulation of
neutrophils, LTB4-stimulated NADPH oxidase activation in guinea-pig
eosinophils appears to be mediated via a tyrosine kinase dependent
mechanism that is esssentially independent of PLD, PI 3-kinase, PLA2 and
MAP kinases. These disparities probably derive from the both the
differences in the stimuli and/or the functional roles of these two cell
types.
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