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and Induces IL-6 by Mouse Macrophages Through Interaction with the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Receptor1
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Department of Tropical Public Health, Harvard School of Public Health, Boston, MA 02115; and
Department of Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523
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Abstract |
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release but increased IL-6. Further, it also induced IL-6
release in a dose-dependent manner from unstimulated macrophages.
Maxadilan increased production of PGE2, and the inhibition
of TNF- was completely abrogated by indomethacin. Others have
recently shown that maxadilan is a selective agonist of the pituitary
adenylate cyclase-activating polypeptide (PACAP) type I receptor.
Treatment with the receptor antagonist PACAP 6–38 blocked maxadilan
activities on macrophages. The natural endogenous ligand, PACAP 38, had
the same effects as maxadilan on TNF- and IL-6 production. Finally,
in a dose- and time-dependent fashion, maxadilan induced the
intracellular accumulation of cAMP in macrophages. Taken together, the
results presented here indicate a modulatory effect of ligands of PACAP
type I receptor on cytokine production by macrophages and suggest that
activation of this receptor, with the subsequent elevation of
intracellular cAMP in macrophages, could participate in a
negative-feedback mechanism that controls certain inflammatory
responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Maxadilan was purified and its coding DNA cloned from the salivary glands of Lutzomyia longipalpis based on its ability to cause erythema (9, 10). The vasodilatory effect of maxadilan is endothelium independent and correlates with an increase of cAMP in smooth muscle cells (11). Maxadilan binds to membrane fractions of rabbit aorta and spleen, and to brain tissues from various species including human, bovine, rabbit, rat, and mouse (12). Maxadilan inhibits splenocyte proliferation and delayed-type hypersensitivity in mice (13), exacerbates murine cutaneous leishmaniasis, and inhibits killing of intracellular L. major by macrophages (our unpublished results). These studies indicate that maxadilan constitutes one of the immunomodulatory substances present in the sand fly saliva.
Moro and Lerner recently reported that maxadilan is a specific agonist of the pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (14). PACAP is a vasoactive neuropeptide with a plethora of biologic properties and is a member of a super family that includes secretin, glucagon, and vasoactive intestinal peptide (VIP) (15, 16). PACAP binds to at least two classes of seven-transmembrane G-coupled receptors: these are type I PACAP-preferring receptors and type II receptors, which also bind VIP with similar high affinity (15, 16). PACAP induces IL-6 release from folliculo-stellate cells from the rat pituitary (17), cortical astrocytes (18), and human placental choriocarcinoma cells (19). Moreover, PACAP inhibits proliferation of mitogen-stimulated splenocytes (20) and IL-10 production by T lymphocytes (21), suggesting a potential effect of this peptide in immune and inflammatory responses.
The present study was designed to examine the effects of maxadilan and PACAP on inflammatory cytokine production by macrophages and the mechanism by which maxadilan had its effects on macrophage functions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals used were: 6-wk-old female BALB/c (Charles River Laboratories, Boston, MA); 6-wk-old male C3H/HeJ (The Jackson Laboratory, Bar Harbor, ME). The animals were housed at the Department of Tropical Public Health, Harvard School of Public Health animal facilities.
Reagents
Reagents were LPS from Escherichia coli serotype 0111: B4, and thioglycollate and indomethacin (Sigma Chemical, St. Louis, MO); DMEM, HBSS, L-glutamine, HEPES, sodium pyruvate, penicillin, and streptomycin (Life Technologies/Life Technologies, Gaithersburg, MD); FCS (HyClone Laboratories, Logan, UT); synthetic rat PACAP 38 and PACAP 6–38 (Peninsula Laboratories, Belmont, CA); and neutralizing anti-IL-6 and anti-IL-I0 (PharMingen, San Diego CA).
The coding DNA of mature maxadilan as reported by Lerner and Shoemaker (10) was amplified by PCR and introduced into pRSET from InVitroGen (Carlsbad, CA) to generate the expression vector XI13–3. An inactive mutant version of the same maxadilan-coding DNA (cysteine 51 to alanine) was fortuitously generated by the same PCR reaction and introduced into pRSET to generate XI13–1 (our unpublished results). E. coli harboring the plasmids were induced for expression as recommended by InVitroGen, to produce recombinant maxadilan having amino terminal fusion partners that contain a hexa-histidine to facilitate purification. The recombinant fusion proteins were purified from inclusion bodies as described (22). All the reagents used in culture, including recombinant and synthetic peptides, contained <10 pg/ml of endotoxin, measured by Limulus assay from BioWhittaker (Walkersville, MD).
Synthetic maxadilan was prepared by the Biopolymers Laboratory in the Harvard Medical School. The amino acid sequence was based on the predicted sequence of mature, secreted maxadilan obtained by sequencing a maxadilan cDNA isolated from a sand fly obtained from Belo Horizonte, Brazil (our unpublished results).
Macrophage cultures
To obtain peritoneal exudate macrophages, mice were injected
with 2 ml of sterile 3% thioglycollate in saline i.p., and after 4
days peritoneal lavage was performed using 10 ml of cold HBSS. After
two washes with HBSS, the cells were resuspended in DMEM supplemented
with 10% FCS and plated in 24-well tissue culture plates at 2 x
106 per well in 1 ml. After 2 h of incubation at
37°C, nonadherent cells were removed by two washes with culture
medium. This adherent population is 
95% Mac-1+
cells (23). Macrophages were then further incubated and treated as
described in the text or figure legends, and cell-free supernatants
were frozen for subsequent cytokine and PGE2
measurement.
Cytokine and PGE2 determinations
Supernatants were tested for TNF- and IL-6 using a sandwich
ELISA according to the manufacturer’s directions. Abs for TNF- and
IL-6 ELISAs, and recombinant mouse TNF- and IL-6, were purchased
from PharMingen. PGE2 was measured using an EIA kit
from Cayman Chemical Co. (Ann Arbor, MI) according to the
manufacturer’s directions.
Measurement of intracellular cAMP
Macrophages were plated as described above. After incubation with isobutylmethylxanthine (1 mM) for 30 min, maxadilan was added to the cultures for 2, 15, 30, 45, or 60 min. The medium was then aspirated and the reaction was stopped by adding 1 ml of cold ethanol to the wells. Samples were centrifuged and frozen until assayed. cAMP contents were determined using an EIA kit from Cayman Chemical Co. according to the manufacturer’s directions.
Statistical analysis
Data were analyzed for significance using Student’s
t test. Data with p 
0.05 were considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been shown that sand fly saliva affects macrophages,
decreasing Ag presentation (7), NO production, and
Leishmania killing (8). Therefore, we investigated whether
maxadilan would affect cytokine production by macrophages treated with
LPS, a potent and well-studied macrophage activator.
Thioglycollate-elicited peritoneal macrophages were pretreated with
increasing concentrations of maxadilan for 2 h, followed by LPS
treatment (500 ng/ml) for an additional 2 or 4 h, and the media
was assayed for TNF- and IL-6 secretion, respectively. In a
dose-dependent fashion, maxadilan markedly decreased LPS-induced
TNF- secretion (Fig. 1
A). Conversely, IL-6
production was markedly enhanced by maxadilan, also in a dose-dependent
manner (Fig. 1B). The maximum inhibition of TNF-
production (about 50%) and enhancement of IL-6 levels (two- to
threefold) was observed at concentrations of 1 to 10 ng of maxadilan/ml
(0.1 to 1 nM).
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). Since the recombinant maxadilan that
we used was made in E. coli, we determined whether the
following additional forms of maxadilan would induce IL-6 production by
macrophages: 1) a mutated recombinant form of maxadilan that lacks
vasodilatory activity, but which is produced in E. coli in a
fashion identical to functional maxadilan, and 2) a synthetic form of
maxadilan. While the mutated maxadilan did not induce IL-6 production
by macrophages, the synthetic maxadilan induced IL-6 production to an
extent similar to bioactive recombinant maxadilan (data not shown). In
addition, to further rule out the possibility that LPS contamination
contributed to our observations, we tested whether maxadilan could
induce IL-6 production by macrophages from C3H/HeJ mice, which are
endotoxin-resistant (24). We found that maxadilan, in a dose-dependent
manner, also induced IL-6 production by C3H/HeJ macrophages (data not
shown).
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release is dependent on
PG
Several studies demonstrated the modulatory effects of
PGE2 and IL-10 on macrophage activation, including the
inhibition of TNF- production (25, 26, 27, 28). Moreover, IL-6 can cause a
reduction in LPS-induced TNF- release from a human monocytic cell
line, from human whole blood, and in vivo (29). Since these three
mediators are produced by macrophages activated with LPS, we determined
the role of PGE2, IL-10, and IL-6 in the maxadilan
inhibition of LPS-induced TNF- production. Treatment with
indomethacin completely abrogated the inhibition by maxadilan of
LPS-induced TNF- release (Fig. 3). On
the other hand, maxadilan was able to inhibit TNF- in the presence
of neutralizing anti-IL-10 Abs (Fig. 3, compare bars 6
and 7) or anti-IL-6 (data not shown).
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production (25) and also a major target of indomethacin, we measured
PGE2 production by macrophages stimulated with LPS in the
presence of maxadilan. The addition of maxadilan consistently led to a
dose-dependent increase in PGE2 release (Fig. 4).
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It has been recently shown that maxadilan is a selective agonist
of the PACAP type I receptor (14). Similar to many other vasoactive
neuropeptides, PACAP mediates a range of biologic activities, including
the induction of IL-6 release from several cell types (17, 18, 19). To test
whether the effects we observed on IL-6 and TNF- production were
mediated through interaction of maxadilan with the PACAP receptor, we
investigated whether the PACAP-competing receptor antagonist PACAP
6–38 blocked the effects of maxadilan on cytokine production. The
addition of 1 µg/ml of PACAP 6–38 completely blocked the inhibitory
effect of 10 ng/ml of maxadilan on LPS-induced TNF- release (Fig. 5A). Likewise, IL-6
production induced by maxadilan was also abrogated (Fig. 5B), indicating that both effects of maxadilan are
mediated by signaling through the PACAP receptor. The addition of the
same amount of CGRP antagonist (CGRP 8–37) did not alter the effects
of maxadilan on IL-6 and TNF- secretion (data not shown)
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release and induces IL-6 production from
LPS-stimulated macrophages
The results obtained with the PACAP receptor antagonist (Fig. 4
)
suggested that PACAP might also modulate TNF- and IL-6 release from
macrophages. PACAP exists in two amidated forms: PACAP 38 and PACAP 27
(30, 31). Since PACAP 38 binds to the PACAP type I receptor with higher
affinity compared with PACAP 27 (32) and constitutes the majority of
the immunoreactive PACAP in several tissues (16), we decided to use
this form in the present study. Preincubation of macrophages with 10
ng/ml of PACAP 38 led to a reduction of LPS-induced TNF- production
similar to that observed with maxadilan (Table I). Finally, PACAP 38 also induced IL-6
release from macrophages and increased LPS-induced IL-6 release
(Table I).
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Activation of the PACAP type I receptor by it ligands markedly
increases the level intracellular cAMP in several cell types (14, 17, 18, 19). Furthermore, the vasodilatory effect of maxadilan correlates
with an increase of cAMP (11). Since elevation of intracellular cAMP
modulates several macrophage functions, we investigated the effects of
maxadilan on this second messenger. Figure 6 shows a time course and a dose response
for maxadilan induction of intracellular cAMP in mouse macrophages.
Within minutes after treating with 10 ng/ml of maxadilan, the levels of
intracellular cAMP increased severalfold (Fig. 6A).
Moreover, the effect of maxadilan on cAMP levels was a dose-dependent
phenomenon (Fig. 6B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by macrophages through
interaction with the PACAP receptor. These conclusions were reached
using multiple corroborating experimental approaches. Both recombinant
(Fig. 2) as well as synthetic maxadilan had similar effects on IL-6
secretion by macrophages. Using LPS-stimulated macrophages, maxadilan
again augmented IL-6 production while it inhibited TNF- secretion
(Fig. 1). These effects on macrophages were mediated by maxadilan
itself (and not another component of our recombinant maxadilan
preparation, such as LPS), since treating macrophages with a mutated
recombinant maxadilan did not modulate cytokine release, and maxadilan
increased IL-6 production even with macrophages obtained from
LPS-unresponsive C3H/HeJ mice (data not shown). Maxadilan exerted its
effects on macrophages through interaction with the PACAP receptor
since the addition of PACAP receptor antagonist, PACAP 6–38,
completely blocked the effects of maxadilan on IL-6, as well as TNF-
release by macrophages (Fig. 5). Finally, synthetic PACAP 38, the
endogenous ligand of the PACAP receptor, modulated cytokine production
by macrophages in a manner similar to maxadilan (Table I).
To determine the mechanisms by which maxadilan exerts its inhibitory
effects on TNF- release from LPS-stimulated macrophages, we treated
the macrophage cultures with indomethacin, neutralizing anti-IL-10
and neutralizing anti-IL-6 Abs. Indomethacin completely abrogated
the inhibitory effect of maxadilan on TNF- production by macrophages
challenged with LPS (Fig. 3), indicating that PGs are involved in the
maxadilan modulation of TNF- production by macrophages. In fact,
treatment of macrophages with maxadilan and LPS led to an increase of
PGE2 in the supernatants compare with the controls
(Fig. 4). It has been reported that IL-10 participates in the
deactivation of LPS-stimulated macrophages by PGE2 (33). In
our experiments, we found that maxadilan was able to inhibit TNF- by
greater than 50% in the presence of anti-IL-10. Treatment with
anti-IL-6 had no effect on TNF- inhibition by maxadilan.
Finally, indomethacin or anti-IL-10 treatment did not interfere
with maxadilan-induction of IL-6 (data not shown). In opposition to the
effect of indomethacin on maxadilan inhibition of TNF- release from
macrophages, the erythema or the vasodilatation of rabbit aorta rings
induced by maxadilan was not blocked by indomethacin (34, 11). Taken
together, these results indicate a dissociation in the involvement of
PG in the effects of maxadilan on TNF- and IL-6 production by
macrophages, as well as in the relaxing activity on smooth muscle
cells. The mechanism by which maxadilan increases PGE2
synthesis remains to be determined.
Inflammatory mediators produced by macrophages are thought to play a
role in the etiology of a variety of pathologic conditions, such as
bacterial, protozoan, and fungal infections, as well as acute and
chronic inflammatory reactions. We originally reported that sand fly
saliva exacerbated infection with L. major in mice and that
the target cell for the saliva seemed to be macrophages (7, 8). The
results presented here extend these observations by showing that a
single protein derived from sand fly saliva, maxadilan, modulates the
production of two proinflammatory cytokines by macrophages, IL-6 and
TNF-, and does so through interaction with the PACAP receptor. We
have since shown that maxadilan also exacerbates L. major
infection in mice and inhibits intracellular killing of the parasite in
macrophages (unpublished results). Thus, maxadilan constitutes at least
one of the immunomodulatory substances present in sand fly saliva.
Regulation of IL-6 production is complex, being mediated by several
signal transduction pathways and involving a number of second
messengers and protein kinases, including intracellular
Ca+, cAMP, and protein kinase C (35, 36, 37, 38). The ability of
both PACAP and maxadilan to stimulate IL-6 production is associated
with increased levels of intracellular cAMP (17–19, Figs. 1B, 2, 6). Indeed, treating with the protein kinase A
inhibitor H89 reduced PACAP-mediated induction of IL-6 secretion by
pituitary cells (17). However, PACAP also activates multiple
intracellular signaling pathways including protein kinase A,
phospholipase C, and protein kinase C translocation (30, 39, 40, 41). These
results suggest that the effects of maxadilan and PACAP 38 on IL-6
release by macrophages are at least in part mediated by the second
messenger cAMP, but that it is likely that both maxadilan and PACAP 38
mediate their effects by triggering more than one intracellular
signaling pathway.
cAMP may also be involved in the mechanism by which maxadilan inhibits
TNF- production by macrophages (Fig. 1A). Several
reports indicate that elevation of intracellular cAMP in macrophages
has an inhibitory effect on LPS-induced TNF- production (25, 33, 42, 43). Current experiments are investigating further the mechanisms by
which maxadilan modulates macrophage function, as well as the effects
of this peptide on inflammatory reactions in vivo.
Previous studies have demonstrated that the vasoactive neuropeptide
substance P stimulates secretion of TNF-, IL-1, and IL-6 from
macrophages (44), and enhances secretion of IL-1 from LPS-stimulated
microglia (45), and TNF- by LPS-stimulated neuroglial cells (46). To
our knowledge, these results constitute the first demonstration that
ligands of the PACAP type I receptor, such as maxadilan and PACAP 38,
have an effect opposite from that of substance P on TNF- release by
macrophages. Furthermore, we have observed that another vasoactive
neuropeptide, calcitonin gene related peptide (CGRP), also inhibits
LPS-induced TNF- production by macrophages in a manner similar to
that of maxadilan or PACAP 38 and in vivo protects mice against a
lethal dose of LPS (our unpublished observations). Therefore, it is
tempting to speculate that there exist two classes of vasoactive
neuropeptides that have opposite effects on TNF- secretion by
macrophages. As a result, these neuropeptides might play a critical
role in counter-regulating the development of inflammatory and immune
responses.
In conclusion, the results presented here suggest that signaling through the PACAP type I receptor on macrophages, with a subsequent rise in intracellular levels of intracellular cAMP, could be involved in blocking inflammatory responses as well as increasing susceptibility to intracellular pathogens. Specifically, these results suggest that the ability of sand fly saliva to exacerbate infection with L. major lies at least in part in its ability to mimic the action of neuropeptides such as PACAP on cytokine release by macrophages. During evolution, sand flies presumably developed anti-inflammatory proteins in their saliva to prevent the vertebrate host from becoming sensitized to the proteins of their saliva. Inadvertently, these same immunosuppressive proteins appear to promote infection with the pathogens sand flies transmit. In addition to sand flies, immunomodulatory factors have been described in the saliva of a number of blood-sucking arthropods including mosquitoes, black flies, and ticks (47, 48, 49, 50, 51). Moreover, tick saliva can enhance virus infectivity (52). It will be interesting to determine whether immunomodulators in the saliva of arthropods other than sand flies will also employ neuropeptide mimicry as one their mechanism of action.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marcelo Bozza, Fundacao Oswaldo Cruz, Nucleo Immunofarmacology, Av. Brazil 4365, Rio de Janeiro, RJ, Brazil CEP 21045-900.
3 Abbreviations used in this paper: NO, nitric oxide; PACAP, pituitary adenylate cyclase-activating polypeptide; CGRP, calcitonin gene-related peptide.
Received for publication September 18, 1997. Accepted for publication October 27, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1ß and TNF production in LPS-stimulated human monocytes: role of cyclic AMP. Cytokine 2:205.[Medline]
from neuroglial cells stimulated with lipopolysaccharide. J. Immunol. 152:819.[Abstract]
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