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Short Communications |
From the Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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IC50 0.2 to 0.9 nmol/L), but not with a
bioinactive ATL isomer. The clinically used CysLT1 receptor
antagonist, Singulair, showed a lower rank order for
competition with [3H]-ATLa (IC50 
8.3
nmol/L). In contrast, LTD4 was an ineffective
competitive ligand for recombinant ALX receptor with
[3H]-ATLa, and ATLa did not compete for
[3H]-LTB4 binding with recombinant
LTB4 receptor. Endogenous murine CysLT1
receptors also gave specific [3H]-ATLa binding that was
displaced with essentially equal affinity by LTD4 or ATLa.
Systemic ATLa proved to be a potent inhibitor (>50%) of
CysLT1-mediated vascular leakage in murine skin (200
µg/kg) in addition to its ability to block polymorphonuclear
leukocyte recruitment to dorsal air pouch (4 µg/kg). These
results indicate that ATL and LTD4 bind and compete with
equal affinity at CysLT1, providing a molecular
basis for aspirin-triggered LXs serving as a local damper of both
vascular CysLT1 signals as well as ALX receptor-regulated
polymorphonuclear leukocyte traffic.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LX and ATL mediate their leukocyte selective actions via their own specific G-protein-coupled receptor, denoted ALX receptor.2 In addition, LX possess vascular regulatory and smooth muscle actions.9,10 These unique responses are mediated via recognition sites distinct from the ALX receptor that are shared with cysteinyl-LT (LTD4/LTC4) in both vascular10 and mesangial11 cells. The slow reacting substances of anaphylaxis (LTC4, LTD4, and LTE4) are of particular interest as they evoke vasculature and smooth muscle responses.1 Along these lines, bronchospastic activity of LTD4 is extensively studied as a target for asthma treatment.12 LTD4/LTC4 recognition sites show cell, tissue, and species variation and are broadly classified as CysLT1 or CysLT2 on the basis of rank order with xenobiotic antagonist,13,14 operational definitions that anteceded molecular cloning and identification of these receptors. Efforts to obtain LTD4 antagonists initially focused on recognition sites and signal transduction.13,15 It is of interest then that both LX and ATL functionally antagonize LTD4/LTC4-induced up-regulation of P-selectin in endothelial cells16 and inhalation of LXA4 antagonizes LTC4-induced airway obstruction in asthmatics.17 Thus, both LX and ATL are of interest as mediators because they might act as local endogenous regulators of LTD4/LTC4 within the vasculature of lung and kidney2,8,10,16 as well as control leukocyte trafficking.2,11
Recently the first human CysLT receptor and human LTB4 receptors (BLT) were cloned and identified14,18,19 using rank order potencies of agonists and antagonists, and a human BLT was overexpressed in transgenic mice.7 LX and ATL mimetics dramatically inhibit BLT amplified responses in these mice. Because the interactions of recombinant CysLT1 receptor with aspirin-triggered mediators (ie, ATL) have not been established, we sought to identify cysteinyl-LT/LX vascular recognition sites and determine its relationship to the recombinant receptors for LTB4 and LXA4. Here, we provide the first direct evidence for a vascular CysLT receptor and its interactions with LXA4 and aspirin-triggered LXA4.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human umbilical vein endothelial cells (HUVECs) and colonic epithelial cells (T84) were cultured and fresh peripheral blood polymorphonuclear leukocytes (PMN) isolated.4,16 HUVECs were exposed to interleukin-1ß (IL-1ß) (1 ng/ml, R&D Systems, Minneapolis, MN) or media alone. Total RNA was isolated (Trizol; Life Technologies, Inc., Grand Island, NY) and reverse transcribed (42°C, 30 minutes) followed by 40 cycles of polymerase chain reaction (PCR) (denaturation at 94°C for 1 minute, annealing at 50°C for 2 minutes, extension at 72°C for 3 minutes) using specific amino- and carboxyl-terminal primers carrying BamHI and XhoI restriction sites, respectively, for CysLT1 receptor (hCysLT1-N: 5'GGCGGATCCATGGA TGAAACAGGA AATCTG-3' and hCysLT1-C: 5'-CGGCT-CGAGCTATACTTTA CATATTTCTTC-3'). These were designed using reported sequence.20 Total RNA was analyzed with primers specific for glyceraldehyde-3-phosphate dehydrogenase, PCR products from each cell type were isolated and their complete nucleotide sequences confirmed (BWH DNA Sequencing Facility, Boston, MA).
Cloning, Functional Expression, and Competition Binding
The confirmed full-length CysLT1 receptor
cDNA was digested with BamHI and XhoI, cloned
into pcDNA3 vector carrying a neomycin-resistant gene (Invitrogen
Corp., Carlsbad, CA) and transfected into HEK293, CHO, and COS-7 cells
using SuperFect (Qiagen Inc., Valencia, CA). Stable transfectants were
obtained by selection with G418 sulfate (0.5 mg/ml; Mediatech, Herndon,
VA) and expression of CysLT1 receptor was
verified by reverse transcriptase (RT)-PCR analysis.
[11,12-3H]-15-epi-16-(para-fluoro)-phenoxy-LXA4
methyl ester ([3H]-ATLa, specific activity
15 to 30 Ci/mmol; a gift of Dr. H. D. Perez, Berlex Biosciences
Inc., Richmond, CA) was prepared with Schering AG (Berlin, Germany)
using acetylenic-LXA4-methyl ester precursor by
Dr. Gay (Scherina AG) and further purified and characterized in
this laboratory by reverse phase-high pressure liquid
chromatography essentially as in Chiang et al.23
Specific activity and radiolabel purity (>97%) were determined by
reverse phase-high pressure liquid radiochromatography equipped with
diode array analyses. Retention times and UV chromophore-matched
synthetic ATLa. Montelukast (Singulair; Merck and Co., Inc., West
Point, PA) was obtained from the Pulmonary Division of Brigham and
Women’s Hospital. Binding studies were performed
essentially as in Sarau et al14
with 1 nmol/L
[14,15,19,20-3H]-LTD4
(specific activity, 158 Ci/mmol; Dupont-New England Nuclear, Boston,
MA), or [3H]-ATLa and 250 to 350 µg of
isolated membrane protein from stable transfectants or rat lungs.
Samples were incubated in 250 µl of 10 mmol/L
piperazine-N,N'-bis(2-ethanesulfonic acid) (pH 6.5; Sigma Chemical Co.,
St. Louis, MO), 10 mmol/L CaCl2, 10 mmol/L
MgCl2, 10 mmol/L glycine, and 10 mmol/L cysteine
for 45 minutes at 25°C as in Sarau et al.14
Nonspecific
binding was determined in the presence of either 100 nmol/L unlabeled
LTD4 or
15-epi-16-(para-fluoro)-phenoxy-LXA4 methyl ester
and routinely accounted for 50% of total binding. Bound and free
[3H]-LTD4 or
[3H]-ATLa was separated by rapid filtration,
under vacuum, through Whatman GF/C filters (Fisher, Pittsburgh, PA).
Filters were washed three times (5 ml) with ice-cold Tris (10 mmol/L,
pH 7.4) and residual
[3H]-LTD4 or
[3H]-ATLa retained on the filters was
quantitated (Beckman scintillation counter; Beckman-Coulter, Inc.,
Fullerton, CA). Total and nonspecific binding for
[3H]-LTD4 or
[3H]-ATLa was 4,800 dpm and 2,400 dpm or
3,400 dpm and 1,800 dpm, respectively. HEK293 cells stably transfected
with either human recombinant LXA4 or
LTB4 receptor were prepared for competition
binding with 1 nmol/L of [3H]-ATLa or
[5,6,8,9,11,12,14,15-3H]-LTB4
(specific activity, 200 Ci/mmol; Dupont-New England Nuclear),
respectively.7,23
Murine Vascular Leakage and Inflammation
BALB/c male mice (Charles River Laboratories, Wilmington, MA), 24.6 ± 0.5 g, n = 32, were anesthetized with pentobarbital sodium (Nembutal; Abbott Laboratories, North Chicago, IL) 50 mg/kg i.p. Sterile 0.9% saline (100 µl) containing either EtOH (vehicle), LTD4 (0.5 µg; Cayman Chemical, Ann Arbor, MI), ATLa (5 µg) alone, or both LTD4 and MK571, a CysLT1 receptor antagonist (5 µg; Cayman Chemical), or aspirin-triggered LXA4 analog, were prepared immediately before injection in left tail vein. Mice were given a single bolus intravenous injection and after 90 seconds mice received a second intravenous injection (left tail vein) of sterile saline (100 µl) containing Evan’s blue (2%, w/v). Animals were euthanized after 10 minutes and entire external ears were removed for quantitation of punctated vascular leakage. Animals within each experimental group were of the same strain, sex, as well as age, and there were no significant differences in total ear area among mice. Ear sections were placed in 800 µl of formamide and subjected to four cycles of freeze/thaw, and incubated at 50°C for 120 minutes to extract Evan’s blue, which was quantitated by monitoring absorbance at 610 nm with a subtraction of nonspecific background (450 to 480 nm). Air pouch experiments were performed as in Hachicha et al21 using intravenous tail vein injections. Differences between individual data points were analyzed using Student’s t-test with a two-tailed distribution; values < 0.05 were taken as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. RT-PCR with specific
CysLT1 receptor primers (see Methods) revealed a
single product 1 kb in mucosal epithelial cells (Figure 1A)
also
present in leukocytes (not shown), but not apparent in vascular
endothelial cells without addition of IL-1ß (Figure 1A)
. Receptor
expression and the appearance of new cellular phenotypes induced by
inflammatory mediators are now recognized as key regulatory
events.4,5,7
When HUVECs were exposed to IL-1ß, a
cytokine that induces many features of inflammation,22
we
observed a dramatic time-dependent induction of RNA for
CysLT1 receptor (Figure 1A)
. Complete sequencing
of the PCR product (1,014 bp) revealed that the nucleotide sequence
amplified from each cell type was identical (not shown) and
corresponded to the recently reported18
human
CysLT1 receptor (Figure 1)
. Comparison of the
deduced amino acid sequence of CysLT1 with the
two other human receptors for lipoxygenase-derived products, namely
LXA4 (ALX2
) and
LTB4 (BLT19
) receptor, showed an
overall 30% homology. ALX and CysLT1 receptor
gave highest homology (47%) in the seventh transmembrane segment that
is associated with ligand recognition23
for eicosanoid
receptors, whereas the first cytoplasmic loop that is associated with
G-protein coupling shows no homology between ALX and
CysLT1 receptor but is highly conserved (56%)
among BLT and ALX receptor (not shown). These findings provide
the first direct evidence for a cytokine-inducible endothelial
cysteinyl-LT receptor, namely CysLT1.
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.
To directly test whether LTD4 and
LXA4 both interact at
CysLT1 we cloned and expressed the vascular
endothelial CysLT1 receptor as stable
transfectants in COS-7 cells. Of the endogenous ligands reported in
competition binding and functional assays with either recombinant human
leukocyte or spleen CysLT1 receptor,
LTD4 is the most potent.14,18
Figure 1
reports results of competition binding with
[3H]-LTD4 and recombinant
CysLT1 receptor. Binding with recombinant human
CysLT1 receptor was specific and high affinity
with COS-7 cell stable transfectants. Isolated COS-7 cell membrane
preparations gave specific binding (apparent IC50
of 0.7 nmol/L for unlabeled LTD4; Figure 1B
),
a value consistent with those reported.18
To determine
whether ATL interacts with CysLT1, a stable
analog of aspirin-triggered LXA4 (ATLa) with
anti-inflammatory activities2
was assessed for its ability
to displace [3H]-LTD4.
Unexpectedly, ATLa that carries a 15-epi configuration displaced
[3H]-LTD4 with
essentially equivalent affinity, IC50 of 0.7
nmol/L, when directly compared to LTD4. Virtually
identical results were obtained with another LXA4
and ATL mimetic 15R/S-methyl LXA4 (not shown).
Together, these findings provide the first direct evidence that ATLa
competes for specific LTD4 binding at recombinant
human CysLT1 found on endothelial cells.
Next, a new tritiated ATLa was prepared to directly assess its affinity
for CysLT1 receptor (see Methods). Both ATLa and
LTD4 competed with high affinity for specific
[3H]-ATLa binding at recombinant endothelial
CysLT1 receptor (Figure 1C)
with an apparent
IC50 of 0.1 nmol/L and 0.9 nmol/L,
respectively. For the purpose of direct comparison, the well-defined
and reported selective CysLT1
antagonist18
montelukast (Singulair, MK476) was assessed
and gave a lower rank order potency for displacing
[3H]-ATLa than either
LTD4 or ATLa with an apparent
IC50 of 8.3 nmol/L (Figure 1C)
. To determine
whether the CysLT1 receptor recognition of
aspirin-triggered LXA4 was stereoselective, we
examined a biologically inactive analog of both
LXA4 and aspirin-triggered
LXA4,10
namely
6S-LXA4
(5S,6S,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic
acid) (see Figure 1C
). This LX isomer (0.01 to 100 nmol/L) did not
displace [3H]-ATLa, indicating that the
rectus chirality at carbon 6, a motif shared by both
LTD4 and ATLa, is essential for
CysLT1 receptor recognition. Neither specific
[3H]-LTD4 nor
[3H]-ATLa binding was observed with wild-type
COS-7 cells. Together these findings indicate that ATLa and
LTD4 directly bind to the
CysLT1 receptor with equal affinity.
To address ATLa actions with the two other recombinant human receptors,
BLT and ALX, competition binding was performed with HEK293 cells stably
expressing each of the respective receptors.
[3H]-ATLa specifically bound to the ALX
receptor with high affinity (Figure 2A)
,
and both unlabeled ATLa and LXA4 competed for
binding with approximately equal affinity with an apparent
IC50 of 0.5 nmol/L and 0.2 nmol/L,
respectively. In contrast, LTD4 was a less
effective ligand for the LXA4 receptor because
its IC50 for [3H]-ATLa
displacement was greater than 3 log orders more than that of the
homoligand ATLa. Values are consistent with our earlier findings
reported with LTD4 and the ALX
receptor.26
Of interest, MK571, a specific
CysLT1 receptor antagonist,18
competed for specific [3H]-ATLa binding at ALX
receptor with equal affinity (IC50 0.3
nmol/L) compared to the homoligand ATLa and LXA4
(Figure 2A)
. For direct comparison,
[3H]-LTB4 specifically
bound to BLT receptor with an apparent IC50 of
5.2 nmol/L for its homoligand LTB4 (Figure 2B
,
inset), whereas ATLa did not compete at physiologically relevant
concentrations (0.1 to 1,000 nmol/L). These results indicate that
LXA4 receptor recognizes ATLa and
LXA4 with essentially equal affinity but that
ATLa does not act selectively at LTB4 receptor.
Moreover, structural motifs shared by aspirin-triggered
LXA4 and LTD4 that are
required for CysLT1 receptor binding are alone
not sufficient for ligand recognition at LXA4
receptor.
|
, inset) gave specific binding with
lung, and both ATLa and LTD4 competed with
approximately equal affinity, giving an apparent
IC50 of 0.2 nmol/L and 0.8 nmol/L,
respectively.
|
. In contrast, mice
treated with the vehicle alone did not show significant vascular
leakage in this tissue. LTD4-stimulated vascular
leakage was dose-dependent (not shown) and inhibited (95 ± 3%,
P < 0.02) by the specific CysLT1
receptor antagonist MK57118
at a dose of 200 µg/kg.
Systemic LTB4 did not induce vascular leakage in
mouse ear tissue within this time interval (n =
3, not shown), whereas LTB4 as a topical agent
stimulates PMN recruitment and subsequent PMN-dependent vascular
leakage at much longer time intervals (eg, 8 to 48 hours) as in Takano
et al.11
When administered alone ATLa did not evoke
vascular leakage, but clearly ATLa treatment inhibited vascular leakage
(53 ± 9% at t = 10 minutes, P <
0.02 when compared to LTD4 leakage) at
intravenous-administered doses as low as 0.2 mg/kg. For purposes of
direct comparison, ATLa was given intravenously (tail vein, 4 µg/kg)
and by 4 hours inhibited TNF-
-induced PMN infiltration by 56 ±
10%, P < 0.02 into the dorsal air pouch (Figure 3B)
.
These are consistent with earlier findings and at this time interval
are held to be mediated by ALX receptors.21 |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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as well as murine
CysLT1 receptor (Figure 3)
provide the first
direct evidence in vivo and in vitro for a novel
vascular site of action and role for LX and aspirin-triggered LX as
endogenous receptor level antagonists of LTD4.
The magnitude and duration of inflammation as well as the host’s
response to reperfusion injury are directly dependent on the presence,
abundance, and activation of specific cellular receptors.7
Here, we found that IL-1ß, a primary pro-inflammatory
cytokine,22
induces RNA expression for
CysLT1 receptor in vascular endothelial cells
(Figure 1)
, suggesting a potentially novel endothelial phenotype and/or
role for this receptor in activated vascular tissue. Cytokine
regulation of eicosanoid receptors represents important regulatory
steps in inflammatory diseases, as both immune function in colonic
mucosa and asthmatic responses in OVA-induced asthma are associated
with induction of epithelial LXA4
receptor4
and prostaglandin D2
receptor.5
Thus, it is noteworthy that
CysLT1 receptor transcripts were also found in
human colonic epithelial cells (Figure 1)
, where a bioaction for
cysteinyl-LT has not yet been firmly established.
In view of the well-appreciated roles of cysteinyl-LT,1
it
is of interest that mimetics of endogenous aspirin-triggered
LXA4 specifically bind to
CysLT1 receptor with apparent equal affinity
(Figures 1–3)
when directly compared to its reported homoligand
LTD4.14,18
Cysteinyl-LT, LX, and ATL
are generated within the vessel lumen during cell-cell interactions,
for example during leukocyte interaction with platelets, or with
inflamed endothelial or mucosal epithelial tissue.2,4
Thus
these potential local-acting lipid mediators can have access to shared
recognition sites (ie, CysLT1 receptor) on
leukocytes, endothelial, epithelial, and smooth muscle cells (Figure 1)
.14,18
In addition, ATL is a regulator of leukocyte
trafficking by acting at the LXA4 receptor
(Figure 2A)
. These findings with labeled analog and ALX receptor are
consistent with earlier results obtained with
[3H]-LXA4 for both human
and murine LXA4 receptors.11,23
ATLa’s potent inhibition of CysLT1 receptor
mediated vascular leakage documented here (Figure 3B)
strongly
indicates that LXA4 and ATLa are also
functionally relevant CysLT1 antagonists in
vivo and provide evidence for a novel fundamentally protective
mechanism that may be in place to dampen overt cysteinyl-LT-generated
signals for leakage. Such protective pathway(s) can be evoked and
amplified by aspirin, which triggers ATL generation via transcellular
biosynthesis between neutrophils and inflamed endothelial cells that
possess up-regulated and acetylated cyclooxygenase II2
at
sites of vascular inflammation (Figure 1C)
. Taken together, these
tools, namely mimetics of LX and novel aspirin-triggered lipid
mediators, because of their prolonged duration of action in
vivo, can help to define local counter-regulatory signals acting
within the microenvironment that are of interest in inflammation,
resolution, and vascular diseases. LX and ATL regulate several
components of interest in human disease. For example, they activate ALX
receptor that 1) inhibits expression of pro-inflammatory
signals2,4,21
; 2) regulates leukocyte trafficking and
sequestration7,8
; as well as 3) act directly as
CysLT1 receptor antagonists established for the
first time at the molecular level in the present experiments. In view
of these findings, endogenous lipid mediators (eg, LX and ATL) could
provide new avenues or alternative approaches to controlling both
vascular inflammatory disorders as well as pathophysiological vascular
events involving elevated levels of LTD4.
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Acknowledgements |
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Footnotes |
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Supported in part by National Institutes of Health grants GM38765 and DE13499 (to C. N. S.). K. G. is the recipient of an NRSA award (F32-AI10389) from the National Institutes of Health and N. C. is the recipient of the McDuffie Postdoctoral Fellowship Award from the Arthritis Foundation.
Accepted for publication September 19, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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