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Inflammation is a beneficial host response to foreign
challenge or tissue injury that leads ultimately to the
restoration of tissue structure and function
1,2
. This
response requires innate immunity and, in some
cases, an adaptive immune response, which are the
two main integral components of the host’s defence
system. Innate immunity not only acts as the first
line of defence against noxious material, but after
recognition of an appropriate stimulus, it provides
the necessary signals to instruct the adaptive immune
system to mount a response. In turn, the adaptive
response relies on the innate immune system to pro-
vide the necessary effectors, in the form of phago-
cytes and granulocytes, to deal with the initiating
stimulus. However, prolonged inflammation can
cease to be a beneficial event and it contributes to the
pathogenesis of many disease states. The chronic
inflammatory disease rheumatoid arthritis is charac-
terized by the accumulation and persistence of
inflammatory cells in synovial joints, which results in
joint damage. This loss of tissue or organ function as
a result of an inappropriate inflammatory response is
also seen in various other diseases, such as chronic
bronchitis, emphysema, asthma, glomerulonephritis,
myocardial infarction and ischaemia reperfusion
injury. By contrast, certain inflammatory diseases
have an intrinsic capacity for complete resolution
without tissue injury — for example, lobar strepto-
coccal pneumonia, which involves the extensive
accumulation of neutrophils, monocytes and
macrophages in the lungs. Studies of patients who
have lobar pneumonia show that most of the lesions
resolve without any evident tissue destruction.
Experiments in animal models of streptococcal
pneumonia show resolution of tissue pathology in
3–4 days
3–5
. Therefore, this type of self-limiting
inflammatory response is under the strict control of
endogenous mechanisms. As continual activation of
the adaptive immune system is the driving force
behind chronic inflammation, it is crucial to identify
the
STOP SIGNALS that are present in self-limiting, self-
resolving inflammatory lesions. These signals might
be used therapeutically to control the activation of
the adaptive immune response and the transition
from acute to chronic inflammation, when these
signals might be absent or become dysregulated. In
pursuit of this goal, recent studies have shown that
certain lipid mediators might have a crucial role in
the resolution of inflammation as endogenous anti-
inflammatory mediators. This review will focus on
an important and largely ignored issue regarding the
regulation of the inflammatory response — that the
ANTI-INFLAMMATORY LIPID
MEDIATORS AND INSIGHTS INTO THE
RESOLUTION OF INFLAMMATION
Toby Lawrence*
‡
, Derek A. Willoughby
‡
and Derek W. Gilroy
‡
The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory
response have become increasingly well characterized. However, little is known about the
mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution
of inflammation is an active process controlled by endogenous mediators that suppress pro-
inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis
and phagocytosis, which are crucial determinants of successful resolution. This review focuses
on this emerging area of inflammation research and describes the mediators and mechanisms
that are currently stealing the headlines.
NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | OCTOBER 2002 | 787
*Laboratory of Gene
Regulation and Signal
Transduction, Department
of Pharmacology, School of
Medicine, University of
California at San Diego,
9500 Gilman Drive, La Jolla,
California 92093-0636, USA.
‡
Department of
Experimental Pathology,
William Harvey Research
Institute, Barts and The
London, Queen Mary’s School
of Medicine and Dentistry,
University of London,
Charterhouse Square, London
EC1M 6BQ, UK.
Correspondence to T.L.
e-mail: tolawrence@ucsd.edu
doi:10.1038/nri915
REVIEWS
STOP SIGNALS
This term was coined to
introduce the concept of a
cellular agonist that acts as an
inhibitor of inflammation.
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REVIEWS
this largely ignored process of resolution have begun to
be elucidated only recently. It has become clear that
endogenous anti-inflammatory mediators reverse vascu-
lar changes and inhibit leukocyte migration and activa-
tion, while promoting the safe removal of inflammatory
cells by apoptosis and subsequent phagocytosis.
There are many mediators that coordinate the initial
events of acute inflammation (
TABLE 1, FIG. 2). Vasoactive
amines, lipid-derived
EICOSANOIDS, cytokines and
chemokines coordinately regulate vascular changes and
inflammatory-cell recruitment
6
. Cell-adhesion mole-
cules facilitate the movement of inflammatory cells
from the peripheral circulation to the inflammatory site.
Pro-inflammatory cytokines, such as tumour-necrosis
factor (TNF) and interleukin-1β (IL-1β), activate sig-
nalling pathways in endothelial cells that regulate the
expression of these adhesion molecules to initiate the
capture of circulating leukocytes
7
.
Endogenous anti-inflammatory mediators
It is well known that the inflamed tissue generates local
pro-inflammatory stimuli to drive acute inflammation,
but there is also systemic and local production of
endogenous mediators that counterbalance these pro-
inflammatory events. Studies in the 1950s and 1960s
identified endogenous anti-inflammatory mediators that
counteract vascular leakage — namely, adrenaline, nor-
adrenaline and 5-hydroxytryptamine
8–10
— and intracel-
lular cyclic AMP, a second messenger induced by several
hormones, inflammatory mediators and cytokines,
which dampens leukocyte activation
11
. Elevation of the
level of intracellular cAMP — by inhibiting the enzyme
system that is responsible for its catabolism (phosphodi-
esterase) — ameliorates immune and non-immune
inflammation in vivo and suppresses various cellular
processes in vitro, including the immunological release
of histamine and leukotrienes from mast cells, mono-
cytes and neutrophils; lysosomal enzymes and reactive
oxygen species from neutrophils; and cytokines and
nitric oxide (NO) from macrophages
12
. These data fur-
ther indicate that cAMP has a central role in the resolu-
tion of inflammation. Perhaps the most powerful
endogenous anti-inflammatory agents to be described so
far are the glucocorticoids. Glucocorticoids and their
synthetic mimetics are used for the treatment of several
chronic inflammatory diseases, including rheumatoid
arthritis, inflammatory bowel disease, asthma, psoriasis
and vasculitis. Most of the actions of glucocorticoids
require binding to cytoplasmic steroid hormone recep-
tors that migrate to the nucleus and antagonize pro-
inflammatory gene transcription
13
.However,glucocorti-
coids also induce the expression of regulatory proteins
that have anti-inflammatory actions, of which the peptide
annexin 1 (previously known as lipocortin 1) has been
well described in vitro and in vivo. Annexin 1 has been
shown to inhibit the production of prostaglandins, as well
as neutrophil and monocyte migration, in vivo
14–16
.
Anti-inflammatory lipid mediators
Research in recent years has uncovered new endogenous
anti-inflammatory lipid mediators that have potent
resolution of inflammation is a highly controlled and
coordinated process that involves the suppression of
pro-inflammatory gene expression, leukocyte migra-
tion and activation, followed by inflammatory-cell
clearance by apoptosis and phagocytosis. We high-
light the role of new endogenous anti-inflammatory
mediators, such as
CYCLOPENTENONE PROSTAGLANDINS
(cyPGs) and LIPOXINS, that might regulate these events.
Acute inflammation: a salutary response
Inflammation is a reaction of the microcirculation that is
characterized by the movement of serum proteins and
leukocytes from the blood to the extravascular tissue.
This movement is regulated by the sequential release of
vasoactive and chemotactic mediators, which contribute
to the cardinal signs of inflammation — heat, redness,
swelling, pain and loss of tissue function
(FIG. 1). Local
vasodilation increases regional blood flow to the
inflamed area and, together with an increase in
microvascular permeability, results in the loss of fluid
and plasma proteins into the tissues. Concomitantly,
there is an upregulation of expression of adhesion mole-
cules on endothelial cells and the release of chemotactic
factors from the inflamed site, which facilitate the adher-
ence of circulating cells to the vascular endothelium and
their migration into the affected area. These tightly regu-
lated events result in a predominance of neutrophils in
the inflamed area at the onset of the lesion, which are
later gradually replaced by mononuclear cells — mainly
monocytes, which then differentiate into macrophages.
These phagocytic cells ingest foreign material and cell
debris. They also release hydrolytic and proteolytic
enzymes, and generate reactive oxygen species that elimi-
nate and digest invading organisms. Finally, the injurious
stimulus is cleared and normal tissue structure and
function is restored. The mediators and mechanisms of
Figure 1 | Cardinal signs of inflammation. This cartoon depicts five Greeks representing the
cardinal signs of inflammation — heat, redness, swelling, pain and loss of function — which are as
appropriate today as they were when first described by Celsus more than 2000 years ago. This
figure was commissioned by D.A.W. and drawn by P. Cull for the Medical Illustration Department
at St Bartholomew’s Medical College.
CYCLOPENTENONE
PROSTAGLANDINS
Prostaglandin metabolites that
are characterized by the presence
of a highly reactive electrophilic
carbon atom in the unsaturated
carbonyl group of the
cyclopentane ring.
LIPOXINS
Leukocyte-derived eicosanoids
generated during the
inflammatory response that act
as downregulatory signals.
EICOSANOIDS
A class of lipid mediator that
have twenty-carbon fatty-acid
derivatives; from the Greek
eicosa, meaning 20. Eicosanoids
are fatty-acid derivatives,
primarily derived from
arachidonic-acid precursors,
that have a wide variety of
biological activities. There are
four main classes of eicosanoid
— the prostaglandins,
prostacyclins, thromboxanes
and leukotrienes — derived
from the activities of
cyclooxygenases and
lipoxygenases on membrane-
associated fatty-acid precursors.
NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | OCTOBER 2002 | 789
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Lipoxins. In contrast to prostaglandins and leuko-
trienes, which are generated by intracellular biosynthe-
sis, lipoxins are generated through cell–cell interactions
by a process known as
TRANSCELLULAR BIOSYNTHESIS
17
.
Nanomolar concentrations of lipoxins inhibit neu-
trophil and eosinophil chemotaxis
18,19
; lipoxin A
4
(LXA
4
), for example, blocks neutrophil migration across
postcapillary venules and inhibits neutrophil entry into
inflamed tissues in animal models
20
. Owing to the very
short half-life of the lipoxins, a range of stable, biologi-
cally active analogues have been designed and tested for
their anti-inflammatory effects in animal models. The
LXA
4
analogue 16-phenoxy-LXA
4
markedly reduced
leukotriene B
4
(LTB
4
)-induced ear swelling in the
mouse, by preventing neutrophil infiltration and reduc-
ing the increased vascular permeability
21
. In contrast to
their inhibitory effects on neutrophil and eosinophil
recruitment, lipoxins are potent chemoattractants for
monocytes
22
; LXA
4
and LXB
4
stimulate monocyte
adherence to vascular endothelium and chemotaxis.
However, lipoxin-recruited monocytes do not gener-
ate superoxide anions or degranulate in the presence
of lipoxins.
The acute inflammatory response is characterized by
the initial recruitment of neutrophils, followed by the
recruitment of monocytes that differentiate into
macrophages. Activated neutrophils that have degranu-
lated are subsequently phagocytosed by monocyte-
derived macrophages, which eventually exit the inflamed
site in the draining lymphatics. Whether the acute
inflammatory lesion resolves depends, in part, on the
activation state of the monocytes. It seems that lipoxins
might have a crucial role in resolving inflammation, not
only by recruiting monocytes to clear the inflamed site of
necrotic and apoptotic neutrophils, but also by regulat-
ing their level of activation and capacity to cause tissue
damage by the uncontrolled generation of reactive
oxygen species
22
. As discussed later, it seems that lipox-
ins might share this role with cyPGs. Lipoxins also
promote the phagocytic clearance of apoptotic cells by
macrophages, which might contribute further to the
resolution of inflammation
23
.
Cyclopentenone prostaglandins. Recent studies in our
laboratory, which have been confirmed by others, indi-
cate that products of
CYCLOOXYGENASE 2 (COX2) have an
important role in the resolution of acute inflamm-
ation
24–26
. These studies show that although COX2 drives
the onset of inflammation through the production of
pro-inflammatory prostaglandin E
2
(PGE
2
), it also
brings about the resolution of inflammation through the
preferential synthesis of the anti-inflammatory cyPG
15deoxy∆
12,14
PGJ
2
(15dPGJ
2
). These studies highlight
several important findings. First, there is a switch
in prostaglandin synthesis from pro-inflammatory
prostaglandins at the onset of inflammation to anti-
inflammatory prostaglandins at the resolution of
inflammation. This has also been shown by Levy and
colleagues
27
, who described a switch from the pro-
inflammatory prostaglandins and leukotrienes that are
produced during the initiation of inflammation to the
immunomodulatory and anti-inflammatory effects.
These can be divided into two classes: the lipoxins and
the cyPGs. The lipoxins are generated in vivo by the
action of
LIPOXYGENASE or the concerted action of lipoxy-
genase and cyclooxygenase enzymes, whereas the
cyPGs are spontaneous prostaglandin metabolites that
are formed by the action of cyclooxygenase
(ONLINE FIGS
1–3)
. Recent research indicates that these two classes of
lipid metabolite are endogenous anti-inflammatory
mediators that promote the resolution of inflammation
in vivo.
LIPOXYGENASE
A nonheme iron dioxygenase
that is the key enzyme in
leukotriene production.
TRANSCELLULAR BIOSYNTHESIS
A biosynthetic pathway that is
dependent on molecules
transferred from one cell to
another.
Table 1 | Mediators that regulate the acute inflammatory response
Mediator class Pro-inflammatory Anti-inflammatory
Amines Histamine, bradykinin Adrenaline, noradrenaline
Lipid mediators PGE
2
, PGI
2
, LTB
4
, LTC
4
PGJ
2
, PGA
1/2
, lipoxins
Complement C3a, C5a C1q receptor
Cyclic nucleotides cGMP cAMP
Adhesion molecules E-selectin, P-selectin, α
v
β
3
integrin, TSP
ICAM1, VCAM1 receptor, PS receptor
Cytokines TNF, IL-1β, IL-6 TGF-β1, IL-10
Chemokines IL-8 (CCL8), GRO/KC, -
MIP1α (CCL3), MCP1 (CCL2)
Steroid hormones - Glucocorticoids
cAMP, cyclic adenosine 3,5 monophosphate; cGMP, cyclic guanosine 3,5 monophosphate; ICAM1,
intercellular adhesion molecule 1; IL, interleukin; LT, leukotriene; MCP1, monocyte chemotactic
protein 1; MIP1α, macrophage inflammatory protein 1α; PG, prostaglandin; PS, phosphatidylserine;
TGF-β1, transforming growth factor-β1; TNF, tumour-necrosis factor; TSP, thrombospondin;
VCAM1, vascular cell adhesion molecule 1.
Onset
Resolution
Neutrophils
Mononuclear
cells
Exudation
30min
1h 6h 24h 48h 72h3h
Histamine
Serotonin
Bradykinin
Complement
TNF
IL-1β
IL-8/KC
LXs
Substance P
PAF
PGs
LTs
MCP1
IL-6
cyPGs
BAX
p53
TGF-β1
Apoptosis
Figure 2 | Theoretical time course of acute inflammation and associated mediators.
This schematic illustrates the cellular kinetics of inflammation and sequential release of mediators,
based on studies of animal models of acute inflammation. Vasoactive amines and lipid mediators
promote exudate formation and oedema; this is followed by the expression of cytokines and
chemokines that activate the endothelium and mediate leukocyte (neutrophil) migration. Finally,
anti-inflammatory mediators, such as lipoxins (LXs) and cyclopentenone prostaglandins (cyPGs),
attenuate cell migration and promote the apoptosis and clearance of leukocytes from the
inflammatory site. The phagocytosis of apoptotic cells by mononuclear cells promotes the further
release of anti-inflammatory mediators, such as transforming growth factor-β1 (TGF-β1). BAX,
BCL-2-associated X protein; IL, interleukin; LTs, leukotrienes; MCP1, monocyte chemotactic
protein 1 (CCL2); PAF, platelet-activating factor; PGs, prostaglandins; TNF, tumour-necrosis factor.
790 | OCTOBER 2002 | VOLUME 2 www.nature.com/reviews/immunol
REVIEWS
migration and macrophage activation are in contrast to
the potent inhibitory effects of lipoxins on neutrophil
recruitment and activation. This might indicate that
lipoxins are early braking signals for the neutrophil
response in acute inflammation, whereas cyPGs pro-
mote the resolution of inflammation through the sup-
pression of pro-inflammatory macrophage function
(BOX 1).
Apoptosis and phagocytosis
The accumulation and persistence of leukocytes is a hall-
mark of chronic inflammation. Apoptosis and the clear-
ance of apoptotic cells have been recognized as impor-
tant mechanisms for the resolution of inflammation
in vivo
43,44
. Apoptosis is a physiological process for the
non-inflammatory removal of cells, and the apoptotic
programme is a conserved feature of all eukaryotic cells.
During apoptosis, cells retain an intact membrane and,
therefore, do not release potentially pro-inflammatory
intracellular components. During the inflammatory
response, recruited granulocytes that undergo apoptosis
retain their granules and lose the ability to degranulate in
response to pro-inflammatory stimuli
43
. Apoptotic cells
express specific surface molecules that allow their recog-
nition and phagocytosis by macrophages
44
.Leukocyte
apoptosis and ingestion by phagocytes such as macro-
phages allows the non-inflammatory clearance of dead
and dying cells from sites of inflammation
(FIG. 3). In ani-
mal models of resolving inflammation, we have shown
that leukocyte apoptosis coincides with the production
and release of cyPGs and other anti-inflammatory media-
tors, such as transforming growth factor-β1 (TGF-β1)
45
.
In vitro studies have shown the ability of 15dPGJ
2
to
promote cell apoptosis
46–48
. Furthermore, the therapeu-
tic effects of 15dPGJ
2
in a rat model of arthritis are asso-
ciated with the induction of synoviocyte apoptosis
28
.
These studies, and work from our laboratory (T.L. and
D.W.G., unpublished observations), indicate that
endogenous PGD
2
metabolites (such as 15dPGJ
2
) might
regulate leukocyte apoptosis during the resolution of
inflammation in vivo. This might account for the anti-
inflammatory properties of these prostaglandin
metabolites.
The signals that promote leukocyte apoptosis are
important for the resolution of inflammation; how-
ever, apoptotic cells themselves can also promote the
resolution of inflammation. Studies by Fadok and col-
leagues
49
have shown that the phagocytic clearance of
apoptotic cells by macrophages promotes the release of
TGF-β1 and suppresses the pro-inflammatory activity
of the macrophages
(FIG. 3). These in vitro studies have
now been extended to in vivo models of inflammation.
The transfer of apoptotic cells to LPS-stimulated lungs
reduced the release of pro-inflammatory mediators
and leukocyte recruitment; this effect could be reversed
by the administration of TGF-β1-neutralizing anti-
serum
50
. Also, the uptake of apoptotic cells by synovial
macrophages has been shown to ameliorate immune-
complex-induced arthritis in mice
51
. Therefore, it is pro-
posed that intrinsic defects in apoptosis and the clearance
of apoptotic cells might lead to chronic inflammatory
anti-inflammatory lipoxins that are produced during
resolution. Second, COX2 is essential for the resolution
of inflammation. Finally, 15dPGJ
2
is a new endogenous
mediator that has potent anti-inflammatory properties.
Since then, several studies in animal models of auto-
immune and inflammatory diseases have indicated that
cyPGs, such as 15dPGJ
2
, have potent immunomodula-
tory and anti-inflammatory properties
28–32
.
The anti-inflammatory properties of cyPGs, similar
to the lipoxins, might relate to effects on cell trafficking
and activation
33,34
. 15dPGJ
2
has been shown to inhibit
TNF-stimulated expression of the adhesion molecules
vascular cell adhesion molecule 1 (VCAM1) and inter-
cellular adhesion molecule 1 (ICAM1) by primary
human endothelial cells. However, the expression of
E-selectin and platelet/endothelial cell adhesion mole-
cule 1 (PECAM1) was unaltered. Furthermore, 15dPGJ
2
inhibited phorbol 12-myristate-13-acetate (PMA)-
and lipopolysaccharide (LPS)-stimulated VCAM1
expression and monocyte binding to human aortic
endothelial cells. Interestingly, 15dPGJ
2
had no effect
on neutrophil adhesion to PMA-activated endothelial
cells; this might be due to the selective inhibition of
adhesion-molecule expression described above.
However, 15dPGJ
2
blocked the adhesion-dependent
oxidative burst of neutrophils in vitro
35
. Also, 15dPGJ
2
has been shown recently to suppress chemokine
expression selectively in vitro; expression of the
mononuclear-cell chemokine monocyte chemotactic
protein 1 (MCP1; also known as CCL2), but not of the
neutrophil-selective IL-8 (CXCL8), was inhibited by
15dPGJ
2
36
. We and others have shown the potent
inhibitory effects of cyPGs on macrophage activation
in vitro
37–42
. Ricote et al.
38
described the suppression of
pro-inflammatory signalling pathways, including
nuclear factor-κB (NF-κB), AP1 and signal transduc-
ers and activators of transcription (STATs), in
macrophages by 15dPGJ
2
. Other studies have shown
the inhibition of pro-inflammatory gene expression
by 15dPGJ
2
and other cyPGs in mouse macrophages
in vitro
40–42
. These effects of cyPGs on monocyte
Box 1 | Anti-inflammatory properties of lipoxins and prostaglandins
Lipoxins
• ↑ Phagocytosis of apoptotic neutrophils
• ↓ Neutrophil and eosinophil migration
• ↓Adhesion-molecule activation and gene expression
• ↑ Monocyte adhesion and chemotaxis
• ↓ Interleukin-8 (CCL8) release by epithelial cells
• ↓ Superoxide production by neutrophils
Cyclopentenone prostaglandins
• ↓ Expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1
on endothelium
• ↓ Monocyte migration
• ↓ Expression of inducible nitric oxide synthase by macrophages
• ↑ Myeloid-cell apoptosis
• ↓ Nuclear factor-κB activation
NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | OCTOBER 2002 | 791
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with PPARγ-negative cell lines have shown that PGD
2
metabolites have modulatory effects that are indepen-
dent of PPARγ
42
. The possible anti-inflammatory roles
of PPARs have been reviewed elsewhere and are not
discussed further here.
How might cyPGs regulate inflammation indepen-
dent of PPARs? The cyPGs are characterized by the
presence of a highly reactive electrophilic carbon atom
in the unsaturated carbonyl group of the cyclopentane
ring
(ONLINE FIG. 3). Through Michael addition reac-
tions, this carbon atom can react with nucleophiles,
such as the free sulphydryl groups of glutathione
(GSH) and cysteine residues that form disulphide
bonds in proteins. Cyclopentenone prostaglandins
have been shown to modify conserved cysteine residues
that are found in both the trans-acting DNA-binding
proteins of NF-κB and elements of the upstream kinase
complex — inhibitor of NF-κB (IκB) kinase (IKK) —
that activates NF-κB
42,57,58
.
NF-κB is thought to have a pivotal role in immune
and inflammatory responses through the regulation of
genes that encode pro-inflammatory cytokines, adhe-
sion molecules, chemokines, growth factors and
inducible enzymes, such as COX2 and inducible nitric
oxide synthase (iNOS). NF-κB also has a pivotal role
in the regulation of cell apoptosis. The consensus
pathway for the activation of NF-κB in response to
pro-inflammatory stimuli such as TNF and IL-1β has
been characterized extensively
(FIG. 4).
Many of the target genes that are suppressed by cyPGs
are regulated by the NF-κB pathway. These include the
genes that encode the adhesion molecules ICAM1 and
VCAM1, and the inducible enzymes iNOS and COX2.
Ricote et al.
38
showed that the inhibitory effects of
15dPGJ
2
on macrophage gene expression are mediated at
diseases. In support of this hypothesis, cytokine-
mediated suppression of apoptosis has been shown in
sputum from patients with neutrophilic lung diseases,
including cystic fibrosis, idiopathic fibrosis and pneu-
monia
52
. A recent study has also described the
impaired clearance of apoptotic cells in patients with
cystic fibrosis and bronchiectasis
53
. In addition, the
impaired uptake of apoptotic cells has been linked to
the pathogenesis of systemic lupus erythematosus
(SLE)
54
.
The promotion of leukocyte apoptosis by cyPGs
and the enhanced uptake of apoptotic cells induced
by anti-inflammatory lipoxins
(BOX 1) indicate that
these endogenous lipid mediators might coordinately
regulate the resolution of inflammation. Therefore,
defects in the production of these mediators might
predispose to chronic inflammation, and their exoge-
nous application might promote the resolution of
inflammatory diseases.
NF-
κκ
B and the resolution of inflammation
The molecular mechanism of the anti-inflammatory
action of cyPGs has been the subject of much debate.
The PGD
2
metabolites of the J
2
series are thought to be
endogenous ligands for peroxisome proliferator-
activated receptor γ (PPARγ). PPARs have been proposed
to negatively regulate inflammation through various
mechanisms
55,56
. However, many of the reported effects
of PPARγ agonists occur at doses far in excess of those
that are required for the activation of the receptor. Studies
that evaluated the PPARγ-dependent inhibition of
macrophage activation in vitro have shown that 15dPGJ
2
is significantly more effective at inhibition than synthetic
PPARγ ligands, despite the fact that it has a relatively
low binding affinity for PPARγ
38
. Similarly, experiments
CYCLOOXYGENASE 2
(COX2). An inducible
cyclooxygenase enzyme that is
thought to be the main producer
of prostaglandins during the
inflammatory response.
b
Apoptotic cell
Scavenger
receptor
PS receptor
Phosphatidyl
serine (PS)
ICAM3
CD14
Macrophage
↑TGF-β1
↓TNF, IL-1β, IL-8
a
Opsonin
FcR or complement
receptor
Macrophage
↑TNF, IL-1β, IL-8
↓TGF-β1
Necrotic cell
Other
ligand
Figure 3 | The two faces of phagocytosis. The non-inflammatory clearance of apoptotic cells (a) compared with the pro-inflammatory ingestion of necrotic cells and
debris (b). a | Macrophages recognize apoptotic cells through specific cell-surface receptors; subsequent phagocytosis promotes the release of anti-inflammatory
mediators, such as transforming growth factor-β1 (TGF-β1), and suppresses the production of pro-inflammatory mediators. b | However, necrotic-cell debris does not
express specific receptors and is phagocytosed through alternative mechanisms, such as Fc receptors (FcR), that promote the release of pro-inflammatory mediators,
such as tumour-necrosis factor (TNF). IL, interleukin; ICAM3, intercellular adhesion molecule 3.
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Besides the role of NF-κB in pro-inflammatory gene
expression, the NF-κB pathway also regulates protection
from cytokine-induced apoptosis
59,60
. This might under-
pin the pro-apoptotic action of cyPGs and contribute
to their anti-inflammatory and immunoregulatory
properties in vivo. For example, expression of the anti-
apoptotic protein BCL-X
L
is regulated by the NF-κB
pathway. 15dPGJ
2
inhibits activation of the BCL-X
L
promoter by NF-κB and promotes the apoptosis of
CD28-co-stimulated primary human CD4
+
T cells
in vitro
47
. Recently, Ward et al.
48
described the induction
of caspase-dependent apoptosis in both neutrophil
and eosinophil granulocytes by 15dPGJ
2
through the
the gene promoter level. Later, it was shown that in
macrophage and lymphocyte cell lines, 15dPGJ
2
inhibited
the activation of IKKβ, which regulates the activation of
NF-κB in response to pro-inflammatory stimuli
41,42,57
.
15dPGJ
2
was shown to alkylate Cys179 of IKKβ, which is
located in the kinase activation loop
57
. The DNA-binding
subunits of NF-κB — p50 (NF-κB1) and p65 (RELA) —
have also been shown to be alkylated at Cys62 and Cys38,
respectively, by 15dPGJ
2
42,58
. These residues are located in
the DNA-binding domains of the proteins and their alky-
lation prevents the activation of gene expression. These
studies indicate that 15dPGJ
2
might inhibit activation of
the NF-κB pathway at many levels
(FIG. 5).
TRANSACTIVATION
The activation of gene
transcription by trans-acting
factors, such as protein
transcription factors, as opposed
to cis-acting DNA elements, such
as enhancers/promoters.
Cytoplasm
iNOS,
VCAM1,
ICAM1
BCL-X
L
COX2
Cys179
Cys38 Cys62
PO
4
15dPGJ
2
Nucleus
Pro-inflammatory
and anti-apoptotic genes
Cell membrane
βα
γ
βα
γ
p65 p50
p65 p50 p65 p50
p65 p50
p65 p50
p65 p50
TNF or IL-1β
IKK
IκBα IκBα
Figure 4 | NF-κB activation in response to pro-inflammatory stimuli. Tumour-necrosis factor (TNF) and interleukin-1β (IL-1β)
stimulate the phosphorylation, ubiquitylation and subsequent degradation of inhibitor of nuclear factor-κB, α (IκBα). This allows the
NF-κB p65–p50 heterodimer to migrate to the nucleus and upregulate the expression of pro-inflammatory and anti-apoptotic genes.
TNF and IL-1β act through distinct cell-surface receptors and signalling pathways that converge on the activation of IκB kinase (IKK),
which consists of three subunits — IKKα, IKKβ and IKKγ. IKKβ is responsible for the activation of NF-κB in response to TNF and IL-1β
through the phosphorylation of IκBα. The cyclopentenone prostaglandin 15deoxy∆
12,14
PGJ
2
(15dPGJ
2
) inhibits the NF-κB pathway at
many levels through the covalent modification of crucial cysteine residues in the IKK complex (Cys179) and the DNA-binding subunits
of NF-κB (Cys38 and Cys62 of p65 and p50, respectively). NF-κB target genes include the COX2 gene; therefore, 15dPGJ
2
generated through COX2 might act as a negative-feedback loop for the expression of COX2 enzyme. This might promote the
resolution of inflammation through the inhibition of pro-inflammatory and anti-apoptotic gene expression. COX2, cyclooxygenase 2;
ICAM1, intercellular adhesion molecule 1; iNOS, inducible nitric oxide synthase; VCAM1, vascular cell adhesion molecule 1.
NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | OCTOBER 2002 | 793
REVIEWS
indicates that 15dPGJ
2
might be particularly attractive
as a pharmacological agent.
In contrast to the well-documented pro-inflamma-
tory role of NF-κB, we have described an active role for
NF-κB in the resolution of inflammation recently
45
.
This involves the recruitment of alternative DNA-binding
complexes that lack transactivation domains, such as
p50–p50 homodimers. Broad-spectrum inhibitors of
the NF-κB pathway, such as antioxidants and protea-
some inhibitors, had the expected anti-inflammatory
actions during the initiation of inflammation; however,
when they were administered after the onset of inflam-
mation, these inhibitors prevented the resolution of
inflammation, which was associated with the inhibition
of leukocyte apoptosis. We hypothesize that this alterna-
tive NF-κB pathway promotes leukocyte apoptosis by
the
TRANSACTIVATION of pro-apoptotic target genes with
co-activating factors. Alternatively, active NF-κB DNA-
binding complexes that lack transactivation domains
might act as dominant-negative inhibitors of anti-
apoptotic gene expression
(FIG. 5). Cyclopentenone
prostaglandins might repress the activation of IKKβ,
leading to a predominance of anti-inflammatory
signalling pathways that are regulated independently
of IKK or by an alternative IKK complex that is not
sensitive to inhibition by cyPGs.
Therapeutic implications
Synthetic lipoxin analogues have shown promise as
therapeutic agents in several disease models
61
.For
example, lipoxin analogues prevent allergen-induced
expression of CCL11 (eotaxin) in vivo, and inhalation
of LXA
4
by asthmatic patients inhibits LTC
4
-induced
airway obstruction. Several studies in animal models of
autoimmune and inflammatory diseases have indicated
that the administration of cyPGs, such as 15dPGJ
2
,
might offer a new approach to anti-inflammatory ther-
apy. The intra-peritoneal administration of 15dPGJ
2
was shown to ameliorate adjuvant-induced arthritis
(AIA) in the rat
28
. These effects were associated with the
suppression of pannus formation and of mononuclear-
cell infiltration into the joint. We have shown similar
effects of both 15dPGJ
2
and PGA
2
in mouse collagen-II-
induced arthritis, which has a different aetiology to that
of AIA in the rat (P. R. Colville-Nash, T.L., D.A.W. and
D.W.G., unpublished observations). A recent study by
Diab et al.
29
has shown that 15dPGJ
2
significantly atten-
uates clinical signs of disease in experimental auto-
immune encephalomyelitis, a mouse model of multiple
sclerosis. Ex vivo culture with 15dPGJ
2
reduced the
ability of encephalitogenic T cells to adoptively transfer
disease. 15dPGJ
2
was also shown to inhibit the prolifera-
tion and cytokine production of antigen (myelin basic
protein)-specific T cells isolated from the spleen. These
data agree with previous studies that showed reduced
proliferation and IL-2 secretion of T-cell clones and
splenocytes after treatment with 15dPGJ
2
30
. Endo-
genous PGJ
2
has also been proposed to modulate lupus
nephritis in vivo. Renal glomerular mesangial cells are
an important source of inflammatory mediators and
cytokines that drive the inflammatory response in lupus
inhibition of IκBα degradation, independent of
PPARγ. Previous studies from this laboratory have
shown that the specific inhibition of NF-κB can
induce granulocyte apoptosis directly and prevent the
delay of apoptosis in stimulated granulocytes
60
.It
should be noted that a direct causal link between
15dPGJ
2
-mediated inhibition of NF-κB and the reso-
lution of inflammation has yet to be proven. However,
the specificity of 15dPGJ
2
for IKKβ and the activation
of NF-κ B in response to pro-inflammatory stimuli
βα
γ
p50 p50
p65 p50
p105
P
IκBα
P
P
P
Ub
Ub
p65 p50
P
IκBα
P
Ub
Ub
Ub
Upstream kinases
Proteasome
Nucleus
NF-κB
Anti-oxidants
cyPGs
IKK
?
?
Proteasome/protease
inhibitors
P
P
P
+ others?
Nature Reviews |
I
mmunology
p65 p50 p50 p50
p50 p50
Pro-inflammatory and
anti-apoptotic genes
Pro-apoptotic genes
+ Co-activators?
Figure 5 | Hypothetical model of an alternative anti-inflammatory pathway of NF-κB
activation. Broad-spectrum nuclear factor-κB (NF-κB) inhibitors that target the proteasome or
undefined upstream signalling events could block potentially beneficial anti-inflammatory pathways
of NF-κB activation. For example, they might block the processing of p105 to p50 and the
assembly of p50–p50 homodimer complexes, which negatively regulate pro-inflammatory gene
expression and might coordinate the expression of an alternative set of NF-κB target genes through
interaction with distinct co-activators. The specificity of cyclopentenone prostaglandins (cyPGs) for
inhibitor of NF-κB kinase-β (IKKβ) might prevent undesirable side effects of inhibitors through the
inhibition of other IKKs or IKK-independent pathways for NF-κB activation. Anti-oxidants have been
shown to inhibit many stages of the NF-κB pathway, including the activation of upstream IKK
kinases and IκB kinase activity. P, phosphate; Ub, ubiquitin.
794 | OCTOBER 2002 | VOLUME 2 www.nature.com/reviews/immunol
REVIEWS
that these events might be regulated by endogenous anti-
inflammatory mediators, such as cyPGs and lipoxins.We
speculate that analogous compounds might be used as
new anti-inflammatory agents for the treatment of
chronic inflammatory diseases. Lipoxin analogues have
already shown potential as anti-inflammatory agents in
animal models of inflammation. Studies that show the
therapeutic activity of the cyPG 15dPGJ
2
in animal
models of autoimmune and inflammatory diseases
indicate that 15dPGJ
2
analogues might also be effective
therapeutic agents.
There has been important progress in defining the
molecular targets of lipoxins with the cloning of the
receptor for lipoxin A
4
and the recent generation of
receptor transgenics, which will be an important tool for
future studies of the anti-inflammatory roles of these
mediators
62
. However, the molecular targets of cyPGs
have yet to be defined in vivo. The recent generation of
antibodies specific for 15dPGJ
2
63
, which have been used
to study the production of this prostaglandin in vitro and
in vivo, will allow further studies of the role of 15dPGJ
2
in
pathology and the possibility of developing blocking
antibodies to define the endogenous roles of these medi-
ators further. It might also be possible to generate anti-
bodies specific for the adduct that is formed by 15dPGJ
2
with specific peptide targets, which could be used to con-
firm the molecular targets of 15dPGJ
2
in vivo.
Further insights into the role of PGD
2
metabolites in
the resolution of inflammation will be provided by stud-
ies of PGD
2
-synthase-knockout and -transgenic mice. It
is predicted that the knockout mice might have defects in
the resolution of inflammation and would, therefore, be
more susceptible to chronic inflammatory and autoim-
mune diseases. By contrast, the transgenic mice would be
resistant to inflammatory irritants and have reduced
disease activity in models of chronic inflammation.
Future studies of the resolution of inflammation will
no doubt uncover further anti-inflammatory mediators
and pathways that might be harnessed for the treatment
of inflammatory and autoimmune diseases.
nephritis. Reilly et al.
31
have shown that mesangial cells
from lupus-prone MRL/lpr mice are defective in PGJ
2
production when stimulated ex vivo, and that this is
associated with exacerbated NO production. The pro-
duction of NO could be blocked by the addition of
exogenous PGJ
2
. The suppressive effects of PGJ
2
on the
production of pro-inflammatory mediators are not con-
fined to the immune system. PGJ
2
has also been shown
to inhibit the β-amyloid-stimulated expression of IL-6
and TNF by microglia in vitro
32
. Alzheimer’s disease is
characterized by the deposition of β-amyloid in the
brain and the activation of microglia that are associated
with the amyloid plaque, so PGJ
2
might also counteract
inflammation in the central nervous system.
The specificity of cyPGs for the IKKβ–NF-κB path-
way makes them particularly attractive therapeutic
agents. As described above, alternative inhibitors of the
NF-κB pathway might prevent leukocyte apoptosis dur-
ing the inflammatory response
45
. The use of such
inhibitors in chronic inflammatory diseases (such as
rheumatoid arthritis) might have adverse side effects.
However, selective inhibitors of the IKKβ pathway and
IκBα degradation would spare other, possibly protective,
signalling pathways
(FIG. 5).
Concluding remarks
It seems paradoxical that certain families of eicosanoid,
particularly those produced by the
CYCLOOXYGENASE PATHWAY,
might have a crucial role in bringing about the resolution
of inflammation. However, there do seem to be circum-
stances when the ‘poacher’ might take the role of unlikely
‘game-keeper’. The concepts that are discussed in this
review highlight an important and largely ignored issue
regarding the regulation of the inflammatory response —
that the resolution of inflammation is a highly regulated
and coordinated process. This process involves the sup-
pression of pro-inflammatory gene expression, leukocyte
migration and activation, followed by inflammatory-
cell apoptosis, phagocytosis and clearance. We have
described experimental evidence both in vivo and in vitro
CYCLOOXYGENASE PATHWAY
A biochemical pathway for the
intracellular production of
prostaglandins from arachidonic
acid.
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Acknowledgements
T. L. would like to acknowledge financial support of the Arthritis
Research Campaign and The Special Trustees of St Bartholomew’s
Hospital Joint Research Board. D. W. would like to acknowledge
financial support of the William Harvey Research Foundation.
Online links
DATABASES
The following terms in this article are linked online to:
OMIM: http://www.ncbi.nlm.nih.gov/Omim/
Alzheimer’s disease | asthma | cystic fibrosis | inflammatory bowel
disease | multiple sclerosis | psoriasis | rheumatoid arthritis | SLE
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
annexin 1 | β-amyloid | BCL-X
L
| CCL11 | CD28 | COX2 |
E-selectin | ICAM1 | IκBα | IKKα | IKKβ | IL-1β | IL-2 | IL-6 | IL-8 |
iNOS | MCP1 | myelin basic protein | NF-κB1 | PECAM1 | PPARγ |
RELA | TGF-β1 | TNF | VCAM1
Access to this interactive links box is free online.
