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The William Harvey Research Institute, Charterhouse Square, London, England
Correspondence: Stephen J. Getting, Ph.D., Department of Biochemical Pharmacology, The William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, England. E-mail: S.J.Getting{at}mds.qmw.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2-melanocyte-stimulating hormone (2-MSH)
and the synthetic agonist MTII inhibited accumulation of KC,
interleukin-1 beta (IL-1ß), and PMN elicited by urate crystals in the
peritoneal cavity. In vitro, macrophage (Mø) activation,
determined as release of KC and IL-1ß, was inhibited by
2-MSH and MTII. The mixed MC3/4-R antagonist SHU9119
prevented the inhibitory actions of 2-MSH and MTII
in vitro and in vivo, whereas the selective
MC4-R antagonist HS024 was without effect. Western blotting also showed
the presence of MC3-R protein on murine peritoneal Mø. Furthermore,
agonism at the MC3-R evoked accumulation of cAMP within the Mø, which
was inhibited by SHU9119. Thus, naturally occurring
melanocortins, as well as the synthetic long-acting compound
MTII, activate MC3-R on peritoneal Mø to inhibit the experimental
inflammatory response.
Key Words: 2-MSH • MTII • KC • IL-1ß • inflammation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-melanocortin-stimulating hormone, -MSH) have long been studied.
-MSH and related peptides possess efficacy in many experimental
models of inflammation, including experimental bowel disease, allergy,
and chronic (mycobacterium-induced arthritis) and systemic inflammation
(endotoxemia) [1
2
]. Clinically, adrenocorticotrophic
hormone (ACTH) was used successfully to manage human gouty arthritis
[3
]. More recently, other fragments derived from the
pro-opio-melanocortin (POMC) gene product displayed inhibitory activity
in a murine model of monosodium urate (MSU), crystal-induced
peritonitis [4
].
The effects of -MSH and other related peptides have been attributed
to inhibition of cytokine synthesis, such as tumor necrosis factor
(TNF-) and interleukin (IL)-1 [5
], and chemokines,
such as KC [4
]. -MSH has also been shown to reduce
up-regulation of adhesion molecules [6
]. A unifying
hypothesis is that all of these effects may be dependent on an
inhibition of nuclear transcription factor 
B activation
[7
]. An important observation of melanocortin peptide
biology is that its anti-inflammatory effects are not a result of
reflex stimulation of the hypothalamo-pituitary adrenalcortical (HPA)
axis with the consequent release of glucocorticoid hormones [8
9
].
Melanocortin receptors (MC-R), of which five have been identified, have been found to have a varied distribution throughout the body, and although some have a distinct role, the function of some others has yet to be elucidated. The MC1-R is found primarily on melanocytes and has been implicated in skin tanning, and the MC2-R, also known as the ACTH receptor, is involved in steroidogenesis [10 ]. Recently, a role for the MC4-R in the control of food intake has been postulated [11 ], whereas no specific actions have been attributed to MC3-R and MC5-R. The human MC3-R was identified and cloned in 1993 and found to be present in brain, placental, gut, and cardiac tissues [12 13 ] but not melanoma cells or adrenal gland [12 ]. The murine MC3-R was identified and cloned in 1994 [14 ] and like the human MC3-R, is expressed peripherally in the heart, brain, and gut [10 12 13 ]. However, it has also been shown that murine macrophages (Mø) express MC3-R mRNA [4 ].
Agonism at the MC3-R leads to cAMP formation and inositol
phospholipid/Ca2+-mediated signaling
[15
]. MC3-R, like the other MC-Rs, interacts with ACTH
and other melanocortins (e.g., and ß MSH) [16
]. In
contrast, 2-MSH has been identified as a selective
agonist at this receptor, causing MC3-R-dependent intracellular
accumulation of cAMP [10
12
17
].
We have shown recently that intraperitoneal (i.p.) injection of MSU
crystals into the mouse peritoneal cavity produce an intense and
long-lasting neutrophil (PMN) accumulation [18
]
accompanied by cytokine release. Activation of MC3-R by nonselective,
POMC, gene-derived products attenuated this inflammatory reaction
[4
]. In the present study, the effects of the putative,
natural, MC3-R agonist 2-MSH [17
] and of
the synthetic derivative MTII [19
] used in the MSU,
crystal-induced peritonitis have been investigated. Both compounds
display a certain degree of selectivity for the MC3-R [11
17
]. We show for the first time anti-inflammatory activity of
these peptides, including inhibition of PMN migration, chemokine, and
cytokine generation. Using a model of macrophage activation and Western
blotting techniques, we determined that MC3-R is the melanocortin
receptor activated by these agonists to modulate the host inflammatory
response.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In vivo model of PMN accumulation
PMN recruitment into the peritoneal cavity was elicited by MSU
crystals, as recently demonstrated [18
]. Mice were
treated i.p. with 3 mg MSU crystals in 0.5 ml phosphate-buffered saline
(PBS), and peritoneal cavities were lavaged at 6 h post-challenge
with 3 ml PBS containing ethylenediaminetetraacetate (EDTA; 3 mM) and
heparin (25 U/ml). Aliquots of the lavage fluids were then stained with
Turk’s solution (0.01% crystal violet in 3% acetic acid), and
differential cell counts were performed using a Neubauer
haematocytometer and a light microscope (Olympus B061). Data are shown
as 106 PMN/mouse. Lavage fluids were then centrifuged at
400 g x 10 min, and supernatants were stored at
-20°C before biochemical determinations (see below).
Enzyme-linked immunosorbent assays (ELISAs) for KC and IL-1ß
Murine KC and IL-1ß levels in peritoneal lavage fluids were
determined using commercially available ELISA purchased from R&D
Systems (Abingdon, UK). In brief, lavage fluids (50 µl) were assayed
for each cytokine and compared with a standard curve constructed with
0–1 ng/ml standard cytokine. The ELISAs showed negligible (<1%)
cross-reactivity with several murine cytokines and chemokines (data
furnished by manufacturer).
Assays of Mø activation
KC and IL-1ß release
A population of peritoneal Mø (>95% pure) was prepared by 2-h
adherence at 37°C in 5% CO2/95% O2
atmosphere in RPMI-1640 supplemented with 10% fetal calf serum (FCS).
The nonadherent cells were then washed off using warm media, and
adherent cells (>95% Mø) were then incubated with MTII and
2-MSH alone or in combination with SHU9119 (9 µM) or
HS024 (9 µM) for 15 min in RPMI-1640 medium. Cells were then
stimulated with 1 mg/ml MSU crystals (a concentration chosen from
previous experiments [4
]), and the cell-free
supernatants were collected 2 h later. KC and IL-1ß levels were
measured by ELISA as described above.
cAMP formation
Møs (1x105) were adhered in 24-well plates as
above and incubated with serum-free RPMI-1640 media containing 1 mM
isobutylmethylxantine and different concentrations of
2-MSH, MTII, or the direct adenyl cyclase activator
forskolin (3 µM). In some experiments, the effect of these peptides
in the presence of the MC3/4-R antagonist SHU9119 (9 µM) was
investigated. After 30 min at 37°C, supernatants were removed, and
cells were washed and lysed. cAMP levels in cell lysates were
determined with a commercially available enzyme immunoassay (Amersham
Ltd., Little Chalfont, Buckinghamshire, UK) using a standard curve
constructed with 0–3200 fmol/ml cAMP.
Drug treatment
2-MSH (YVMGHRFWDRFG; 1–30 µg/mouse equivalent
to 3.17–95 nmol) and the MC3/4-R agonist MTII
(Ac-Nle4-c[Asp5,
D-Phe7,Lys10]NH2
ACTH4–10; 1–30 µg/mouse equivalent to
0.93–27.9 nmol) were administered subcutaneously (s.c.) 30 min prior
to MSU crystals. In some experiments, the agonists were tested in the
presence of the MC3/4-R antagonist SHU9119
(Ac-Nle4-c[Asp5,
D-2Nal7,Lys10]NH2
ACTH4–10) of which 9 nmol (10 µg/mouse) was given i.p.
30 min prior to MSU crystals [4
]. In vitro,
MTII and 2-MSH were added in the range of 0.93–27.9
(1–30 µg/ml) and 9.5–317 µM (3–100 µg/ml), respectively. In
some experiments, the MC3/4-R antagonist SHU9119 and MC4-R antagonist
HS024
(Ac-Cys3-Nle4-Arg5,D-2Nal7,Cys11)--MSH-NH2
[20
] were also used at a final concentration of 9 µM
and added to cells 10 min prior to agonist stimulation. All peptides
were purchased from Bachem Ltd. (Saffron Walden, Essex, UK) and stored
at -20°C prior to use. All peptides were dissolved in sterile PBS
(pH 7.4). Control animal groups or control cells received equal volumes
of this vehicle compared with treated animals and cells.
Western blotting analysis
Protein was isolated from samples of mouse or rat peritoneal Mø
in PBS containing EDTA (3 mM), leupeptin (0.39 mg/ml), and
phenylmethylsulfonyl fluoride (PMSF; 10 mM). Protein levels were then
determined (Biorad Protein Assay, Bio-Rad Laboratories, Hemel
Hempstead, UK), and 50 µg protein was mixed with 0.125 M Tris-HCl (pH
6.8), 2mM EDTA, 4% sodium dodecyl sulfate (SDS), 10 %
mercaptoethanol, and 20% glycerol and boiled for 10 min prior to
loading and running on an 10% polyacrylamide gel (Protogel, National
Diagnostics, Ashby De La Zouche, Leicestershire) for 60 min at 100 V.
Protein was transferred onto polyvinylidene difluoride (PVDF) membranes
(Amersham) by semi-dry blotting (Bio-Rad) for 60 min using a
Tris/glycine buffer containing 20% methanol. Membranes were then
blocked overnight at 4°C by immersion in a 5% nonfat dried milk
solution made up in PBS containing 0.1% Tween 20. Membranes were then
incubated for 2 h at 4°C in a 5% nonfat dried milk solution
with an affinity-purified goat polyclonal antibody (1:200 final
dilution) raised against a peptide mapping the carboxy terminus of the
human MC3-R (sc-6878, Santa Cruz Biotechnology, Santa Cruz, CA). This
goat polyclonal MC3-R antibody showed cross-reactivity with mouse and
rat but did not cross-react with MC1-R, MC2-R, MC4-R, and MC5-R of any
species (data supplied by the manufacturer). Following one 15-min and
three 5-min washes in PBS and Tween 20 (0.1%), the membrane was
incubated for 1 h with a horseradish peroxide-conjugated donkey
anti-goat immunoglobulin G (IgG) secondary antibody [1:5000 in 0.1%
bovine serum albumin (BSA) in PBS and 0.1% Tween; Santa Cruz
Biotechnology]. After another 15-min and three 5-min washes in
PBS/Tween, blots were incubated with electrochemical luminescence (ECL)
solution (Amersham) for 1 min and then exposed to autoradiographic film
for detection of chemiluminescence. CruzTM molecular weight markers
were also used (sc-2035, Santa Cruz Biotechnology).
Statistics
Data are shown as mean ± SE of n
distinct observations. Statistical differences were calculated on
original data by analysis of variance (ANOVA) followed by Bonferroni
test for intergroup comparisons [21
] or by unpaired
Student’s t-test (two-tailed) when only two groups were
compared. A threshold value of P < 0.05 was taken as
significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2-MSH inhibit PMN accumulation in
experimental gout2-MSH caused a dose-dependent attenuation
of neutrophil migration into the peritoneal cavity. The most effective
dose was 9.3 and 31.7 nmol for MTII and 2-MSH,
respectively, and higher doses led to a plateauing effect (Figs. 1A
and
2A). As a marker of inflammation, the CXC chemokine KC and the cytokine
IL-1ß were measured in cell-free lavage fluids. The natural and
synthetic agonists of the MC3-R were able to inhibit KC (Figs. 1B
and 2B) and IL-1ß (Figs. 1C
and 2C)
release into the peritoneal cavity.
In naïve mice, the number of PMN and levels of KC and IL-1ß
were below the detection limits of these assays (unpublished results).
The effects of MTII and 2-MSH were dependent on the dose
of peptide used, and the higher the dose, the greater the degree of
inhibition, such that 9.3 nmol of MTII and 31.7 nmol
2-MSH already produced a near-maximal effect. On all
these inflammatory parameters, MTII was more effective than
2-MSH, producing higher degrees of inhibition.
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2-MSH and MTII anti-migratory
properties2-MSH, respectively. MTII and
2-MSH inhibited MSU crystal-induced PMN recruitment by
37% and 39%, respectively. An inhibition of KC and IL-1ß release in
the lavage fluids by MTII (43% and 63%) and 2-MSH
(80% and 39%), respectively, was also measured. Treatment of mice
with the MC3/4-R antagonist SHU9119 alone essentially had no
significant effect on KC, IL-1ß, or PMN accumulation when compared
with the PBS control group. However, SHU9119 abrogated the
anti-migratory properties of MTII and 2-MSH (Figs. 3A
and 4A
) as well as KC (Figs. 3B
and 4B) and IL-1ß
release (Figs. 3C
and 4C)
.
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2-MSH inhibit Mø cytokine and chemokine
release2-MSH was tested, significant reductions of KC levels
were obtained at concentrations of 95 and 317 µM (Table 2
). However, on IL-1ß release, a greater degree of inhibition of
80% was observed at the highest concentration of 317 µM
2-MSH (Table 2)
. In the presence of the mixed MC3/4-R
antagonist SHU9119, the inhibitory effects of 2-MSH were
abrogated on both parameters measured (Table 2)
. However, the peptide
was still active in the presence of the MC4-R antagonist HS024.
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2-MSH
(1.4–95 µM) caused increases in cAMP accumulation dependent on the
concentration of peptide used (Fig. 6A
). MTII (9.3 µM) also caused an increase in cAMP accumulation within the
Mø. In both cases, incubation of the top concentrations with SHU9119
(9 µM) abrogated this potentiation in cAMP formation (Fig. 6B) . In
addition, SHU9119 had no effect on forskolin-induced cAMP accumulation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2-MSH,
cleaved from the larger POMC gene, has been proposed to be the natural
agonist for the MC3-R in view of a good degree of selectivity for this
receptor [12
17
]. The synthetic compound MTII is a
substituted cyclic form of the core heptapeptide region
ACTH4–10 common to -MSH and ß-MSH and to a certain
degree 2-MSH. MTII has been shown to have selectivity
toward the MC3-R and MC4-R in murine models of feeding
[11
].
Pretreatment of mice with 2-MSH and MTII prior to MSU
crystal injection caused an inhibition of PMN migration into the
peritoneal cavity dependent on the dose used. This inhibition was
associated with a reduction in KC and IL-1ß levels in the
inflammatory exudates. These peptides almost certainly exerted their
anti-migratory effects via inhibition of the release of chemokines and
cytokines rather than their action. This is because peptides that
contain the core sequence ACTH4–10 are unable to inhibit
PMN migration elicited by KC and IL-1ß [4
9
]. The
ability of melanocortins, especially -MSH, to inhibit PMN migration
and the release of pro-inflammatory cytokines has been well-documented
[4
8
22
23
24
]. However, this is the first time that
synthetic (MTII) and natural (2-MSH) agonists of the
MC3-R have been shown to inhibit PMN migration and the release of
pro-inflammatory cytokines. Therefore, these peptides can be added to
the list of melanocortins able to inhibit the experimental inflammatory
process.
The use of the mixed MC3/4-R antagonist SHU9119 [11
25
]
confirmed that the effects of MTII and 2-MSH were
mediated by the MC3-R or MC4-R or both. MTII and 2-MSH
were evaluated in the presence or absence of the antagonist at a dose
previously shown to abrogate the inhibitory effects of
ACTH4–10 on PMN migration and chemokine release [4
9
]. SHU9119 blocked the ability of these peptides to inhibit
PMN migration, KC, and IL-1ß release, as measured at the 6-h time
point. A confirmation of the causal role of MC3-R was obtained in a
series of in vitro experiments. The use of in
vitro experiments was also a necessity because
2-MSH can produce alterations in the cardiovascular
system [26
27
]. These alterations consist of transient
changes in blood pressure, heart rate, and blood flow [28
29
]. Therefore, the anti-inflammatory effects seen after MSU
crystal injection could be secondary to changes in blood flow and shear
rate in the microcirculation.
The Mø has been shown previously to be the target for the actions of
melanocortin peptides [30
31
32
33
34
]. MTII and
2-MSH inhibition of Mø activation was measured with an
assay of chemokine and cytokine inhibition. The model of in
vitro-cultured Mø activation was determined because it could be
coupled to the in vivo data with the release of KC and
IL-1ß. MTII and 2-MSH caused significant inhibition of
MSU crystal-stimulated KC and IL-1ß release. These data complement
other studies demonstrating that melanocortin peptides can inhibit
cytokines and chemokine [4
8
22
23
24
]. This is likely
to be consequent to blockade of gene transcription as demonstrated for
KC mRNA in the mouse liver [35
]. Therefore, melanocortin
peptides showing a higher degree of selectivity for MC3-R suppress Mø
functions. The next set of experiments was conducted with the mixed
MC3/4-R antagonist SHU9119 [4
11 ] and the more
selective MC4-R antagonist HS024 [20
]. HS024 is 20-fold
more selective for the MC4 over MC3-R, and it is inactive at any other
melanocortin receptor [20
]. The MC3/4-R antagonist
SHU9119 abrogated the effects of MTII and 2-MSH on KC
and IL-1ß release; whereas the more selective MC4-R antagonist HS024
failed to show any inhibitory effect. Therefore, these data are
strongly suggestive that the peptides 2-MSH and MTII act
on MC3-R and not MC4-R in our experimental conditions.
The Mø has long been known to be deactivated by the full peptide ACTH
(e.g., inhibition of interferon--mediated tumoricidal activity
[23
] and latex bead phagocytosis [30
])
and more recently by -MSH [8
]. Thus, MC3-R expression
and functioning on mouse peritoneal Mø were investigated. Western
blotting analysis confirmed that MC3-R was present on murine and rat
peritoneal Mø. To our knowledge, this is the first time that MC3-R
expression is monitored on primary cells by this biochemical technique.
The data obtained were confirmed further by reduction of the 43 kDa
band in the presence of the MC3-R-blocking peptide. Importantly, MC3-R
protein expression could be detected in basal conditions, and this
complements the presence of the MC3-R message as detected by reverse
transcriptase-polymerase chain reaction (RT-PCR) [4
]. It
also provides further support to the conclusion that the Mø is the
target cell of these peptides. In cell depletion experiments, the core
heptapeptide ACTH4–10 inhibited MSU crystal-induced
inflammation in mast cell-depleted mice but not Mø-depleted animals
[9
].
MC-Rs are coupled positively to adenyl cyclase, and their activation
leads to cAMP formation [12
]. MTII and
2-MSH caused cAMP accumulation within the peritoneal
Mø, and this effect was blocked in the presence of the MC3/4-R
antagonist SHU9119. Therefore, MC3-R present on peritoneal Mø are
linked to cAMP. It is worth noting that other studies described ACTH
binding to murine leukocytes associated with intracellular accumulation
of cAMP [36
].
The research in the field of anti-inflammatory melanocortins is
hampered by the lack of selective tools. We demonstrate here
anti-inflammatory data obtained with MTII and 2-MSH,
peptides with a certain degree of selectivity toward the MC3-R,
in vivo and in vitro. This is supported first by
the first determination of MC3-R protein expression in a primary cell
type. Further support is derived from the combined use of the
antagonists SHU9119 and HS024. We propose that a selective agonist at
MC3-R expressed on the Mø could be a drug endowed with
anti-inflammatory activity, with possible applications in gouty
arthritis and other inflammatory conditions.
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ACKNOWLEDGEMENTS |
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Received July 11, 2000; revised September 11, 2000; accepted September 21, 2000.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
P < 0.05 peptide versus
SHU9119.