 |
Introduction |
Lipid and protein mediators of inflammation, such as cytokines and chemokines, have a profound impact on
the formation and actions of each other (1). In particular, the
cytokines TNF-
and IL-1
play major roles in inflammation, septic shock, and tissue injury. PMN perform a range
of well appreciated, specialized functions, including chemotaxis, generation of reactive oxygen species (ROS)1, and
biosynthesis of potent lipid mediators (2). In this regard, TNF-
stimulates PMN to transcribe and release cytokines
such as IL-1
, enhances leukotriene biosynthesis, and upregulates adhesion molecules (3). As PMN represent ~70% of
the peripheral blood leukocytes and are in many instances
the initial cell type recruited to interstitial sites, they are now
considered a significant source of "proinflammatory" cytokines, including TNF-
and IL-1
. These as well as other
PMN-derived cytokines and chemokines can, in turn, affect the course of inflammatory and immune responses (4). In certain clinical settings, including respiratory distress syndrome, myocardial reperfusion injury, gout, and rheumatoid arthritis (RA), PMN contribute to ongoing damage of
host tissues (2, 5, 6). Thus, it is of interest to understand the
complex relationships between lipid mediators and TNF-
-evoked PMN responses in order to gain insight for new
approaches in controlling these events.
The contribution of leukotriene (LT)B4 in inflammation
is well established in view of its potent ability to attract
PMN. Another series of bioactive lipid mediators, termed
lipoxins (LX) and aspirin-triggered lipoxins (ATLs), inhibits, within the nanomolar range, fMLP- and LTB4-stimulated PMN adhesion and transmigration (1, 7) and hence
represent proposed counterregulatory signals operative in
the resolution of inflammatory sites (10). In human tissues,
three main pathways are known for LX generation. An intraluminal source of LX is exemplified by PMN-platelet
interactions that utilize sequential transcellular biosynthetic
routes with the PMN 5 lipoxygenase (LO) product LTA4
and platelet 12-LO. The mucosal and/or interstitial source
of these eicosanoids involves cell-cell interactions with leukocyte 5-LO and 15-LO present in, for example, eosinophils, gastrointestinal or tracheal epithelium controlled by
IL-4 and IL-13 (for review see reference 1). The third and most recently elucidated pathway also represents a novel
mechanism of action for aspirin that triggers the endogenous
biosynthesis of 15R epimers of native LX, termed ATL,
generated via transcellular biosynthesis (8).
LX are generated during cell-cell interactions via transcellular biosynthesis (1) and are produced in vivo during
angioplasty and in immune complex glomerulonephritis
(11). LXA4 is also present in nasal lavage fluids of aspirin-sensitive asthmatics and is generated by leukocytes from patients with asthma and RA (12, 13). Like most autacoids
and lipid mediators, LX are rapidly biosynthesized, act within
a local microenvironment, and are rapidly enzymatically inactivated. To advance our understanding of LX and ATL
roles in vivo, metabolically stable LX analogues were designed that resist rapid inactivation and mimic the in vitro
actions of naturally occurring LX and ATL (14). Here, we
report that these compounds are potent inhibitors of
TNF-
-driven PMN-associated inflammatory events in
vitro as well as in vivo. Moreover, LXA4-ATL inhibit
macrophage inflammatory peptide (MIP)-2 and IL-1
yet
stimulate the local appearance of IL-4 within exudates.
 |
Materials and Methods |
Human and mouse rTNF-
and human rGM-CSF were obtained from Boehringer Mannheim. Dulbecco's PBS (Mg2+- and
Ca2+-free), RPMI 1640, and FCS were purchased from BioWhittaker, Inc. Ficoll-Hypaque was from Organon Teknika Corp., and
HBSS was purchased from GIBCO BRL. BSA, dextran, antibiotics, L-glutamine, cytochrome C, superoxide dismutase, and zymosan were obtained from Sigma Chemical Co. The assessment of
human IL-1
in supernatants was performed by using an immunometric assay with acetylcholine esterase (Cayman Chemical). Murine IL-1
was assessed using an ELISA from Endogen. ELISAs for
IL-4 and IL-10 were from Amersham Corp.; MIP-2 and IL-13
ELISAs were from R & D Systems, Inc. LXA4 and ATL metabolically stable analogues were prepared and characterized, including
nuclear magnetic resonance spectroscopy, as in reference 14. Concentrations of each LX analogue were determined using an extinction coefficient of 50,000/M/cm just before each experiment and
used as methyl esters. Where indicated, statistical analyses were performed using nonpaired t test (two-tailed), and significance was
considered to be attained when P < 0.05.
Preparation of Human PMN Suspensions and Superoxide Anion
Generation.
Venous blood from healthy donors was collected
under sterile conditions using acid citrate dextrose as an anticoagulant, and PMN were isolated as in reference 15. PMN were suspended in cold (4°C) Hank's medium (supplemented with 1.6 mM
Ca2+, 0.1% FCS, 2 mM L-glutamine, 1% penicillin, and 2%
streptomycin, pH 7.4). Cell preparations were >98% PMN, as
determined by Giemsa-Wright staining. Cell viability was >98%
for freshly isolated PMN and
92% for PMN incubated for 20 h,
as determined by trypan blue exclusion using light microscopy.
To examine superoxide production, PMN (106/ml) were placed
at 37°C (3 min) and then exposed to vehicle (0.1% ethanol) or
synthetic LXA4, 15R/S-methyl LXA4, or 16-phenoxy-LXA4 for
5 min at 37°C. Before adding TNF-
(50 ng/ml), PMN were incubated with cytochrome C (0.7 mg/ml) for 10 min at 37°C. Superoxide dismutase-dependent reduction of cytochrome C was
terminated by rapidly placing tubes in an ice water bath. The extent of cytochrome C reduction in each supernatant was determined at 550 nm in reference and compared with control values
obtained when superoxide dismutase was added before a stimulus
or vehicle control. Cytochrome C reduction was quantitated using the extinction coefficient of 21.1/mmol/liter.
RNA Isolation and Northern Blot Analysis.
Total RNA extraction and Northern blot analyses were performed as in reference 7.
pSM320 vector containing cDNA for IL-1
was purchased from
American Type Culture Collection.
Murine Air Pouches.
6-8-wk-old male BALB/c mice were
obtained from Taconic Farms, Inc. Air pouches were raised on
the dorsum by subcutaneous injection of 3 ml of sterile air on
days 0 and 3. All experiments were conducted on day 6 (16). Individual air pouches (one per mouse) were injected with vehicle
alone (0.1% ethanol), TNF-
, 15R/S-methyl-LXA4, or TNF-
plus 15R/S-methyl-LXA4, and each was suspended in 1 ml endotoxin-free PBS immediately before injection into pouch cavities.
At given intervals, the mice were killed, and individual air pouches
were lavaged three times with sterile PBS (1 ml). The exudates
were centrifuged at 2,000 rpm (5 min), and the supernatants were
removed. Cell pellets were suspended in PBS (200 µl) for enumeration and assessed for viability. 50 µl of each cell suspension
was mixed with 150 µl 30% BSA and then centrifuged onto microscope slides at 500 rpm for 5 min using a cytospin centrifuge,
air dried, and stained with Giemsa-Wright.
 |
Results and Discussion |
Inhibition of TNF-
-stimulated Superoxide Generation.
TNF-
, although a modest agonist of O2
generation by
human PMN, is a physiologically relevant stimulus for the
generation of ROS by nonadherent human PMN (17) that
can play critical roles in local tissue injury during both inflammation and reperfusion (17). In Fig. 1, we evaluated the impact of LXA4- and ATL-related bioactive stable
analogues on TNF-
-stimulated superoxide anion production. TNF-
gave a concentration-dependent increase in
superoxide anion dependence (Fig. 1, inset) with nonadherent PMN; therefore, TNF-
(50 ng/ml) was used to
examine the analogues. Native LXA4 and the analogues
(15R/S-methyl-LXA4 and 16 phenoxy-LXA4) inhibited TNF-
-stimulated superoxide anion generation in a concentration-dependent fashion. Their rank order of potency
at 10 nM was 15R/S-methyl-LXA4 (81.3 ± 14.1% inhibition)
16-phenoxy-LXA4 (93.7 ± 3.2%) > LXA4 (34.3 ± 2.3%). 15R/S-methyl-LXA4 covers both LXA4 and ATL
in structure, and 16-phenoxy-LXA4 is an LXA4 analogue
(Fig. 1). Each analogue competes at the LXA4R (7). LXA4,
15R/S-methyl-LXA4, and 16 phenoxy-LXA4, at concentrations up to 1 µM added to cells alone, did not stimulate
generation of ROS (data not shown). 15R/S-methyl-LXA4 and 16-phenoxy-LXA4 were approximately three times more
potent than native LXA4 and proved to be powerful inhibitors of TNF-
-stimulated superoxide generation by PMN.
However, neither LXA4 nor its analogues inhibit PMA
(100 nM)- or fMLP (100 nM)-stimulated O2
production
(n = 3; data not shown). Inhibition of ROS by LXA4 and
its analogues is of interest in a context of ischemia/reperfusion, where ROS are held to be primary mediators of tissue
injury (15).

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Fig. 1.
LXA4 and ATL stable analogues inhibit TNF- -stimulated superoxide generation by human neutrophils. Human PMN were incubated
with vehicle alone or indicated concentrations of LXA4, 15R/S-methyl-LXA4, or 16-phenoxy-LXA4 for 5 min and then with TNF- (50 ng/ml)
for an additional 10 min. Values are the mean ± SEM for LXA4 (n = 3),
15R/S-methyl-LXA4 (n = 4), or 16-phenoxy-LXA4 (n = 3). LXA4 and
analogues, at all concentrations tested, led to a statistically significant inhibition of TNF- -induced IL-1 appearance (P < 0.01). Inset: TNF-
concentration-dependent superoxide production. Human PMN were incubated with indicated concentrations of TNF- . Values are the mean ± SEM (n = 3). TNF- alone (50 ng/ml) gave 0.76 ± 0.12 nmol cytochrome C-reduced cells per 106 cells compared with fMLP (10 nM), another
physiologically relevant stimulus, that gave 6.02 ± 0.05 nmol cytochrome
C-reduced cells per 106 cells.
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Suppression of TNF-
-stimulated IL-1
Release.
PMN
express and release interleukin-1
, which is a potent pro-inflammatory cytokine (20). Therefore, we next investigated the actions of native LXA4 and its analogues on TNF-
-induced IL-1
release. Incubation of PMN with physiologically relevant concentrations of TNF-
, GM-CSF, or
phagocytic particles (zymosan) resulted in a concentration-dependent increase in the levels of IL-1
present in supernatants. Approximate EC50 for each agonist were: TNF-
,
10 ng/ml; GM-CSF, 10 U/ml; and zymosan, 100 µg/ml. Native LXA4 specifically inhibited TNF-
-induced IL-1
release (Fig. 2 A), whereas similar amounts of IL-1
were
released in the presence or absence of LXA4 when PMN
were exposed to either GM-CSF or zymosan. The viability
of PMN exposed to ATL or TNF-
was examined using
trypan blue exclusion. PMN exposed to these agents did not
dramatically increase their staining (Fig. 2 A, inset), suggesting that the ATL did not reduce PMN viability during the time courses of these experiments.

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Fig. 2.
LXA4 and stable analogues inhibit TNF- -induced IL-1 production in human neutrophils. (A) PMN were incubated with (TNF- [10 ng/
ml]; stippled bar) plus vehicle or TNF- plus LXA4 (100 nM; black bar) as denoted for 20 h at 37°C and 5% CO2. Supernatants were collected, and
IL-1 was quantitated by ELISA. Results are expressed as mean ± SD of duplicates and are from one experiment representative of n = 3. (B) PMN
were incubated for indicated periods of time in the presence of increasing concentrations of 15R/S-methyl-LXA4. Values represent the mean ± SEM,
n = 3. At all time intervals tested, TNF- induced a significant appearance of IL-1 over vehicle-treated cells (*P < 0.01).
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PMN were exposed to increasing concentrations of
15R/S-methyl-LXA4, 16-phenoxy-LXA4, or native LXA4
in the presence of TNF-
(10 ng/ml) or vehicle alone. At
a concentration of 100 nM, 15R/S-methyl-LXA4 inhibited
~60% of IL-1
release, and 16-phenoxy-LXA4 at equimolar levels gave ~40% inhibition (values comparable to those
obtained with native LXA4; data not shown). Time course
and concentration dependence were carried out with 15R/S-methyl LXA4 (Fig. 2 B). At 10 nM, 15R/S-methyl-LXA4 gave clear, statistically significant inhibition, which
was evident within 6 h and more prominent after 24 h (Fig.
2 B). Inhibition of IL-1
by these LX analogues was, at
least in part, the result of a downregulation in gene expression, because the IL-1
messenger RNA levels in cells
treated with TNF-
(10 ng/ml) plus 15R/S-methyl-LXA4
(100 nM) were decreased by ~60% when compared with
cells treated with TNF-
alone (Fig. 3). Therefore, as IL-1
and TNF-
are two cytokines that are considered important in inflammation, the inhibition of IL-1
observed
(Figs. 1 and 2) suggested that 15R/S-methyl-LXA4 might
exert a potent in vivo anticytokine action (vide infra).

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Fig. 3.
15R/S-methyl-LXA4 downregulates TNF- -triggered IL-1
gene expression. PMN were incubated with either 0.1% ethanol (vehicle)
or 15R/S-methyl-LXA4 at 10, 100, and 1,000 nM, in the presence or absence of TNF- (10 ng/ml), for 6 h at 37°C. Northern blot analyses were
performed in order to detect IL-1 mRNA. The results presented are
from one experiment, which is representative of two others performed
with different donors.
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Involvement of LXA4R.
To investigate whether LXA4R
was involved in the regulation of TNF-
-stimulated IL-1
release, the rabbit polyclonal antibodies against a portion
of the third extracellular domain (ASWGGTPEERLK) of
LXA4R prepared earlier (21) were used. PMN were incubated with ~50 µg/ml of either preimmune protein
A-purified IgG or IgG directed against LXA4R for 1 h
at 4°C before exposure to TNF-
(10 ng/ml) and 15R/S-methyl-LXA4 (100 nM). Anti-LXA4R antibodies prevented IL-1
release by TNF-
, suggesting that the third
extracellular loop plays a crucial role in LXA4R activation
(Fig. 4). 15R/S-methyl-LXA4 inhibited ~50% of IL-1
release. When added together, anti-LXA4R antibodies and
15R/S-methyl-LXA4 in the presence of TNF-
did not
further inhibit IL-1
appearance, and neither anti-LXA4R
antibodies nor 15R/S-LXA4 alone stimulated significant
amounts of IL-1
to appear in supernatants. The results of
these experiments are twofold: first, they indicated that the
inhibitory action of 15R/S-methyl-LXA4 is transduced via
LXA4R and second, that the anti-LXA4R antibodies alone
activate LXA4R and lead to inhibition of IL-1
release.

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Fig. 4.
Involvement of LXA4R. PMN were
incubated with either IgG purified from preimmune
serum (50 µg/ml) or anti-LXA4R (50 µg/ml) for
1 h at 4°C and then exposed to agonists for 12 h at
37°C and 5% CO2. Values are expressed as mean ± SD from an experiment performed in triplicate,
which is representative of three distinct experiments,
each performed with different donors (*P < 0.01).
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Inhibition of TNF-
-directed Leukocyte Trafficking In Vivo.
As TNF-
evokes leukocyte infiltration in a chemokine-dependent fashion in the murine six-day air pouch (16, 22),
we evaluated the impact of 15R/S-methyl-LXA4 in this
model to determine whether LXA4 or ATL also intersects
the cytokine-chemokine axis in vivo. 15R/S-methyl-LXA4
is the most subtle modification to native LXA4 and ATL
structure, with addition of a methyl at carbon 15. Murine TNF-
(10 ng/ml) caused a transient infiltration of leukocytes to the air pouch in a time-dependent fashion, with maximal accumulation at 4 h. 15R/S-methyl-LXA4 at 25 nmol
inhibited the TNF-
-stimulated recruitment of leukocytes
to the air pouch by 62% (Fig. 5). Inhibition was evident at
1 h and maximal between 2 and 4 h. At these intervals, a
>60% reduction in leukocyte infiltration was noted that
remained significantly reduced at 8 h (Fig. 5, inset). Injection of pouches either with vehicle or the analogue alone
did not cause a significant leukocyte infiltration. Also, inflammatory exudates were collected 4 h after injection with vehicle alone, TNF-
, 15R/S-methyl-LXA4 alone, or TNF-
plus 15R/S-methyl-LXA4, and cell types were enumerated. In the six-day pouches given TNF-
, PMN constituted the major cell type present within the exudates at 4 h
and ranged from 80 to 85% of total cell number. Administration of both 15R/S-methyl-LXA4 and TNF-
into the
six-day air pouch cavity inhibited migration of PMN and
eosinophils/basophils as well as mononuclear cells (Table I).
Of interest is the finding that administration of 15R/S-
methyl-LXA4 alone evoked a small but statistically significant increase in mononuclear cell influx (Table I), a result that is consistent with earlier in vitro observations (23)
in which specific stimulation of monocyte and inhibition of
PMN chemotaxis have been observed.

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Fig. 5.
Inhibition of TNF- -induced PMN infiltration in murine
air pouches. 1 ml of sterile PBS containing 0.1% ethanol, TNF- , 15R/S-methyl-LXA4, or TNF- plus 15R/S-methyl-LXA4 was injected into the
pouches, and the exudates were collected at indicated time periods. The
total number of leukocytes was counted as described in Materials and
Methods. The results are expressed as mean ± SEM from three different
mice for each point. At all time intervals, TNF- induced a significant
leukocyte infiltration into the air pouch cavity (P < 0.05). *Statistically
different from TNF- -treated, vehicle-, or 15R/S-methyl-LXA4-treated
cells (P < 0.01).
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Cytokine-Chemokine Profiles.
Because MIP-2 is the major
chemokine involved in recruiting PMN to the air pouch
after injection of TNF-
(16), we determined the action of
15R/S-methyl-LXA4 in this TNF-
-induced chemokine- cytokine axis. MIP-2 and IL-1
are important proinflammatory cytokines, and IL-4, IL-10, and IL-13 possess immunomodulatory properties (24, 25). Exudates from selected
time intervals were collected, and cell-free supernatants
were assessed for the presence of these murine cytokines.
TNF-
induced maximal detectable amounts of MIP-2 and
IL-1
within 90 min (data not shown). 15R/S-methyl-LXA4 (25 nmol) inhibited TNF-
-stimulated MIP-2 and
IL-1
release by 48 and 30%, respectively (Fig. 6). 15R/S-methyl-LXA4 alone in the air pouch did not stimulate
MIP-2 or IL-1
release. In sharp contrast, 15R/S-methyl-LXA4 stimulated the appearance of IL-4 within the exudates.
This stimulation of IL-4 was observed both in the absence as
well as the presence of TNF-
. Neither IL-10 nor IL-13 was
detected within the pouch exudates. These results demonstrate that administration of 15R/S-methyl-LXA4 modified the cytokine-chemokine axis in TNF-
-initiated acute inflammation, and, interestingly, this reorientation of the cytokine-chemokine axis paralleled the reduction in leukocyte
infiltration.

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Fig. 6.
15R/S-methyl-LXA4 redirects the TNF- -induced cytokine-chemokine profile in vivo. Experiments were conducted as described in the Fig. 5 legend. Quantitation for IL-1 , IL-4, IL-10, IL-13,
and MIP-2 was performed using ELISA with air pouch cell-free exudates.
The results are expressed as mean ± SEM from three different mice for
each time point. Changes in IL-1 , MIP-2, and IL-4 were significant at
all tested time intervals (P < 0.01). At 1 h, air pouches injected with
TNF- alone generated 384 ± 12 pg/pouch of MIP-2 and 14.9 ± 2.3 pg/pouch of IL-1 . 15R/S-methyl-LXA4 alone induced 42.7 ± 0.7 pg/
pouch of IL-4.
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Several different strategies have been explored in an attempt to attenuate nondesirable action of TNF-
in inflammatory diseases and ischemia/reperfusion injury, including
treatment of patients suffering from RA with rTNF-
R
linked to human Ig as a fusion protein (26). Different
steroidal and nonsteroidal drugs (27) to alleviate the pain
and the severity of inflammatory responses are extensively
used. However, certain clinical settings, such as reperfusion
injury, are still not well controlled, and new therapeutic
agents are needed. Our results indicate that LXA4 and ATL,
as evidenced by the actions of their metabolically stable analogues (16-phenoxy-LXA4 and 15R/S-methyl-LXA4), are
potent cytokine-regulating lipid mediators that can also impact the course of inflammation initiated by TNF-
and
IL-1
. These two cytokines are considered to be key components in orchestrating the rapid inflammatory-like events
in ischemia/reperfusion (within minutes to hours) and are
major cytokines in RA and many other chronic diseases.
Interestingly, in an exudate and skin wound model, 15R/S-methyl-LXA4 not only inhibited the TNF-
-elicited
appearance of IL-1
and MIP-2 but also concomitantly
stimulated IL-4 (Figs. 5 and 6). This represents the first observation that lipoxins induce upregulation of a potential
"antiinflammatory" cytokine such as IL-4. Hence, it is of
particular interest that IL-4 inhibits PMN influx in acute antibody-mediated inflammation (28) and inhibits H2O2 production by IFN-
-treated human monocytes (29). IL-4 is
also an active antitumor agent and, most recently, was shown
to be a potent inhibitor of angiogenesis (25). It is thus likely
that the increase in IL-4 levels stimulated by metabolically
stable LX analogues may in part mediate some of the in vivo
impact of LXA4 and aspirin-triggered 15-epi-LXA4, a finding that provides a new understanding of the relationship between antiinflammatory cytokines and lipid mediators.
In conclusion, LXA4 and ATL appear to be involved in
controlling both acute as well as chronic inflammatory responses. The results presented here support the notion that
aspirin may exert its beneficial action in part via the biosynthesis of endogenous ATL that can in turn act directly on
PMN and/or the appearance of IL-4. Thus, LX-ATL can
protect host tissues via multilevel regulation of proinflammatory signals.
Address correspondence to Charles N. Serhan, Center for Experimental Therapeutics and Reperfusion Injury, Thorn Building for Medical Research, 7th Fl., Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Phone: 617-732-8822; Fax: 617-278-6957; E-mail: cnserhan{at}zeus.bwh.harvard.edu
These studies were supported in part by National Institutes of Health grants, nos. GM-38765 and P01-DK50305 (to C.N. Serhan), and a grant from Schering AG (to C.N. Serhan and N.A. Petasis). M. Pouliot is
the recipient of a Centennial fellowship from the Medical Research Council of Canada.
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