Microbes and Infection, 3, 2001, 141−147
© 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S1286457900013617/REV
Inhibitory neuropeptide receptors on macrophages
Doina Ganeaa*, Mario Delgadoa,b
b
a
Department of Biological Sciences, Rutgers University, 101 Warren Street, Newark, NJ 07102, USA
Departamento of Biologia Celular, Facultad de Biologia, Universidad Complutense, Madrid 28040, Spain
ABSTRACT – The immune response, both in innate and adaptive immunity, is controlled at
several levels, including signaling from the central nervous system. Neuropeptides released within
the lymphoid organs modulate the immune response, either as stimulators or inhibitors. The subject
of this review is the description of macrophage-expressed receptors of inhibitory neuropeptides. We
describe the inhibitory effects on macrophage function for several neuropeptides, the receptors that
mediate those activities, and the molecular mechanisms initiated by some of these receptors in terms
of transduction pathways and transcriptional factors. © 2001 Éditions scientifiques et médicales
Elsevier SAS
neuropeptides / macrophages / receptors
1. Neuropeptide sources
in the lymphoid organs
Two different neuropeptide sources exist in the lymphoid organs, i.e. the peptidergic innervation and the
immune cells themselves. In addition, some of the neuropeptides can be released from the hypothalamic-pituitary
axis as hormones or prohormones and arrive in the lymphoid organs via the circulation. A number of studies
established and characterized the peptidergic innervation
in the lymphoid organs, with neuropeptide Y (NPY) colocalized with norepinephrine (NE) in the sympathetic fibers,
substance P (SP) and calcitonin gene-related peptide
(CGRP) closely overlapping anatomically, but not necessarily colocalized in the sensory innervation, and vasoactive intestinal peptide (VIP) present in the cholinergic
innervation [1–3]. In addition, a less abundant galanin
(Gal), somatostatin (Som), and opioid innervation was also
reported [1–4]. The peptidergic terminals were shown to
be in anatomical apposition to the immune cells, particularly to macrophages.
Various immune cells also express and secrete neuropeptides. Here we will review only the macrophage/
monocyte neuropeptide production. Macrophages from
various organs and tissues were shown to express mRNA
and secrete SP, corticotropin-releasing factor (CRF), propiomelanocortin (POMC)-derived peptides such as alphamelanocyte stimulating factor (α-MSH), ACTH, and
β-endorphins (End), Som, CGRP, NPY, and atrial natri-
*Correspondence and reprints.
E-mail address: dganea@andromeda.rutgers.edu (D. Ganea).
Microbes and Infection
2001, 141-147
uretic peptide (ANP) [5–14]. Stimulation with LPS, cytokines, or in the case of thymic macrophages with dexamethasone, leads to increased neuropeptide production
[6, 8, 10–14].
2. General effects of neuropeptides
on macrophage activation and functions
Numerous studies reported on the effects of neuropeptides on macrophage function in vivo and in vitro. Table I
summarizes the neuropeptide effects on macrophage
phagocytosis, adherence/chemotaxis, cytokine production, production of nitric oxide and oxygen radicals and
antigen presentation. Whereas some neuropeptides such
as SP, PRL, NT and NPY stimulate most macrophage
functions, others act as inhibitors especially for the production of proinflammatory cytokines and nitric oxide/
oxygen radicals. Since the focus of this review is on
inhibitory neuropeptide receptors, we will discuss only
the neuropeptides with well established inhibitory effects
on macrophage function in either innate or adaptive immunity.
3. Inhibitory neuropeptide receptors
on macrophages
3.1. Melanocortin receptors (MCRs)
The POMC gene product is processed in a tissuespecific manner giving rise to a variety of peptides, including ACTH1-39, α-MSH and β-endorphins. As mentioned
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Ganea and Delgado
Table I. Effects of neuropeptides on macrophage functions.
Neuropeptide
NT
PRL
SP
NPY
Opioids
BetaEND
Macrophage
treatment
Phagocytosis
Adherence/
chemotaxis
resting
resting
LPS or resting
increase
increase
resting
increase
increase
LPS, GM-CSF
stimulation
LPS
LPS
LPS, IFN-γ,
GM-CSF
inhibition
stimulation
inhibition
SOM
LPS
increase
CRF
αMSH
VIP/PACAP
inhibition
LPS
LPS,IFN-γ
LPS ± IFN-γ
above, macrophages are capable to express the POMC
gene, and to process the translated product leading to the
secretion of α-MSH and β-endorphins [6, 9]. ACTH and
especially α-MSH have potent direct anti-inflammatory
activities, in addition to the induction of glucocorticoids
by ACTH via the hypothalamic-pituitary-adrenal axis. Both
ACTH and α-MSH bind to a class of closely related,
cAMP-inducing, G-protein-coupled receptors, called the
MCRs. In contrast to MC1-R and MC2-R that are expressed
primarily in melanocytes and adrenal cortex, respectively,
the other three receptors are widely distributed both in
brain and the periphery. The expression of MCRs has been
demonstrated in both macrophages and neutrophils, and
in macrophage cell lines. Peritoneal macrophages express
MC3-R that mediates the inhibition of phagocytosis and
chemokine release by ACTH-related peptides [24], and
stimulated neutrophils express MC1-R that mediates the
inhibition of chemotaxis by α-MSH [42]. The murine
macrophage cell line Raw 264.7 also expresses MC1-R
that mediates the inhibitory effect of α-MSH on iNOS
expression and subsequent nitric oxide production [34],
and the human monocytic THP-1 cells express MC1-R,
MC3-R and MC5-R, with MC1-R mediating the inhibition
of TNF-α by α-MSH [43].
3.2. Atrial natriuretic peptide (ANP) receptors
The natriuretic peptide family consists of three members, ANP and BNP (brain natriuretic peptide), both of
cardiac origin, with endocrine functions, and CNP (C-type
142
↑IL-1, IL-6
↑IFN-γ, IL-10
↑TNF-α, IL-12
↓TGF-β1
Nitric oxide
and/or oxygen
radicals
↓TNF-α
↓TNF-α, IL-1β
↓IL-1,TNF-α
↓IL-12 p40
↑IL-6, IL-10
↓IL-6, TNF-α
↓IFN-γ
↓TNF-α
↓ TNF-α, IL-1
↑IL-10
↓TNF-α,IL-6
↓IL-12p40
↓IFN-γ, TGFβ
↑IL-10
Antigen
presentation
References
increase
increase
[15]
[16]
[17–19]
increase
[20]
↑IL-1, IL-10
↑IL-6, TNF-α
↑TNF-α
↑IL-12p35
Met-ENK
ACTH
ANF
CGRP
Cytokines
↑MHCII
[21, 22]
[23]
inhibition
inhibition
inhibition
↓B7.2 ↓MHCII
↓stimulation of
T cells
[17, 24, 25]
[26–28]
[29, 30]
[10, 31, 32]
inhibition
inhibition
↓B7, CD40
[33]
[34, 35]
inhibition
↓B7.1/B7.2
[36–41]
natriuretic peptide), produced mostly in brain where it
plays a paracrine role. Peritoneal, bone marrow-derived,
and thymic macrophages produce all three natriuretic
peptides, and macrophage stimulation has a regulatory
effect, increasing ANP and particularly CNP production,
and decreasing BNP expression [14]. Three receptors have
been identified for the natriuretic peptide family. NPR-A
and NPR-B (which favor ANP and CNP binding, respectively) are coupled to guanylate cyclase and lead to intracellular cGMP accumulation. In contrast, NPR-C serves as
a clearance receptor which binds and internalizes natriuretic peptides from blood but does not stimulate the
guanylate cyclase. Macrophages (peritoneal, bone
marrow-derived, cell lines such as Raw 264.7 and J774)
express all three receptors, but only ANP inhibits TNF-α,
IL-1β and nitric oxide production through the induction of
cGMP [28]. Nitric oxide production is affected through a
reduction in NF-jB binding to its transactivating site in the
iNOS promoter [26], and the inhibition of TNF-α and
IL-1β by ANP is mediated by NPR-A and reduction in both
NF-jB and AP-1 binding [28].
3.3. CGRP receptors
The primary transcript for calcitonin is processed to
calcitonin mRNA in thyroid C cells, and to CGRP mRNA
in brain and the peripheral nervous system. Macrophages,
specifically Langerhans cells, also express CGRP [12].
Based on recognition of different antagonists, two types of
CGRP receptors have been identified, CGRP1 and CGRP2
Microbes and Infection
2001, 141-147
Inhibitory receptors of mononuclear phagocytes
receptors. The transduction pathways used by the CGRP
receptors depend on their localization, with most receptors in the periphery using the adenylate cyclase pathway
to activate cAMP. Macrophages express CGRP receptors,
and in most cases the effects of CGRPs are mediated
through the CGRP1 receptor. For example, the potentiation of IL-6 production, and the inhibition of TNF-α production and of the antigen-presenting function, are mediated through the CGRP1 receptors and the cAMP/PKA
pathway [44]. Dendritic cells, both immature and mature,
also express mRNA for CGRP1 receptor that mediates the
reduction in B7.2, MHC class II, and in the stimulation of
allogeneic T cells. These effects, however, appear to be
dependent on Ca2+ mobilization rather than cAMP induction [45]. Actually, Parameswaran et al. [46] reported
recently that cells transfected with the CGRP1 receptor
respond to CGRPs by increases in cAMP, ERK and p38
MAPK activity. Activation of ERK is induced by either
cAMP or PI3-kinase, whereas activation of p38 is entirely
cAMP-dependent. Therefore, both cAMP and Ca2+ mobilization might be required for an optimal response to
CGRPs through the CGRP1 receptor.
3.4. Somatostatin receptors
Somatostatins were isolated from hypothalamus, as
well as from pancreatic and gastrointestinal tissues. In
addition, activated macrophages and macrophage cell
lines express pre-pro-SOM mRNA and synthesize the
mature peptide [11, 47]. In vivo, SOM was induced in
macrophages from popliteal lymph nodes following LPS,
IFN-γ, or LPS plus IFN-γ injections [10]. Five different
types of SOM receptors have been identified to date. All
are coupled to G proteins and inhibit adenylate cyclase
and Ca2+ fluxes. In peritoneal macrophages, functionally
active concentrations of SOM progressively increase
cGMP levels [48]. Although mRNA for all SOM receptors
was identified in various lymphoid tissues, Sst2A appears
to be the prevalent receptor in thymic macrophages, granuloma macrophages from schistosome-infected mice and
from patients with sarcoidosis, and in synovial macrophages from patients with rheumatoid arthritis. SOM inhibits the production of a number of pro-inflammatory agents,
such as TNF-α, IL-6, IFN-γ and nitric oxide [10, 31, 32].
Although the mechanisms by which SOM acts as an
anti-inflammatory agent are poorly understood, SOM
exerts both a direct effect on the immune cells and an
indirect one through glucocorticoids. A recent report [49]
demonstrates that SOM does not upregulate the glucocorticoid receptors (GRs) on macrophages, but increases glucocorticoid binding and signaling by stabilizing the
GR-associated induced heat shock protein Hsp90. This
stabilization is mediated through a reduction in calpain
activity.
3.5. CRF receptors
CRF is widely distributed in the CNS, particularly in the
hypothalamic nuclei, as well as in various organs in the
periphery, including thymus and spleen. Macrophages
represent the major CRF-positive cells in the immune
organs [7]. CRF inhibits both T-cell proliferation and the
secretion of TNF-α and IL-1β by activated macrophages
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2001, 141-147
Forum in Immunology
[33]. Three receptor subtypes, CRF1, CRF2a and CRF2b,
have been identified in brain, pituitary and spleen, where
they are restricted to macrophage-rich regions. The CRF
receptors are G-protein-coupled, and induce intracellular
cAMP. In Kupffer cells, urocortin, a peptide homologous to
CRF, was shown to inhibit TNF-α production directly, in a
corticosteroid-independent manner, through cAMP
increases [33].
3.6. VIP (vasoactive intestinal peptide)
and PACAP (pituitary adenylate
cyclase-activating polypeptide) receptors
The effects of VIP and PACAP on immune cells, and
specifically on macrophages, are well documented. In
addition to the VIP-ergic innervation of the lymphoid
organs, activated T cells, and particularly Th2 effectors are
the major VIP sources in the immune system ([50]; see
notes added in proof (1)). VIP and PACAP affect many
levels of the immune response in vivo and in vitro, from
macrophage-mediated innate immunity, to antigen presentation, proliferation and differentiation of T cells,
activation-induced T-cell apoptosis, and CD8+ T-cell cytotoxicity [36, 51–54]. Here we will review only the effects
on activated macrophages. VIP and PACAP act as general
anti-inflammatory agents, inhibiting the production of
proinflammatory cytokines such as TNF-α, IL-12, IL-6 and
the induction of iNOS, and stimulating the production of
the anti-inflammatory cytokine IL-10 [37–41]. In vivo, VIP
and PACAP exert similar effects, and protect mice in a high
endotoxemic model of septic shock (reviewed in [51]). In
addition to the effects on cytokine and nitric oxide production, VIP and PACAP also reduce the expression of the
costimulatory molecules B7.1 and B7.2 in activated macrophages, and inhibit their costimulatory activity for naïve
T cells [36]. The effects of VIP and PACAP are mediated
through specific receptors. Three receptors, VPAC1,
VPAC2 and PAC1 have been cloned and characterized
[55]. VPAC1 and 2 bind both VIP and PACAP with similar
affinity, and are coupled primarily to the cAMP/PKA pathway. PAC1 binds PACAP with an affinity 300–1 000-fold
higher than VIP, and is coupled to both adenylate cyclase
and phospholipase C. Studies with murine peritoneal macrophages and macrophage cell lines and with the human
monocytic cell line THP-1 indicate that VPAC1 and PAC1
are constitutively expressed, whereas VPAC2 is induced
upon activation ([39, 56] and unpublished results). In both
peritoneal macrophages and the Raw 264.7 cells, VIP and
PACAP affect TNF-α, IL-10, NO, IL-12p40 and B7 expression primarily through VPAC1. In contrast, the inhibition
of IL-6 is mediated through PAC1 (reviewed in [51]).
Extensive studies have been done on the molecular mechanisms involved in the inhibition of TNF-α, IL-12p40, IL-10
and iNOS expression by VIP/PACAP. The stimulatory effect
on IL-10 transcription is cAMP-dependent, and mediated
through an increase in CREB (cAMP-regulatory element
binding protein) [41]. In contrast, the VIP/PACAP inhibition of TNF-α, iNOS and IL-12p40 expression occurs
through two transduction pathways, a cAMP-dependent
and a cAMP-independent pathway. For TNF-α, the cAMP
independent pathway leads to a reduction in NF-jB binding and the cAMP-dependent pathway results in a change
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in the composition of the CRE-binding complex from
high
c-Jun/lowCREB to highCREB/lowc-Jun [57]. Optimal activation of iNOS and IL-12p40 requires both LPS and IFN-γ.
For these two genes, VIP and PACAP inhibit IRF-1 binding
in a cAMP-dependent manner and NF-jB binding in a
cAMP-independent manner [40, 56]. Recently, we showed
that the inhibition of IRF-1 binding is due to a reduction in
IRF-1 transcription mediated through the inhibition of
Jak1/2-STAT1 phosphorylation/activation [58] (figure 1).
Also, we demonstrated that the VIP/PACAP promotes JunB
and inhibits c-Jun phosphorylation through effects on the
MEKK1/MEK4/JNK pathway [59] (figure 2). Replacement
of c-Jun with JunB in transcriptional complexes results in
the transcriptional inactivation of various cytokine promoters. Finally, VIP/PACAP affects sNF-jB at various levels (figure 3). A cAMP-independent pathway is responsible
for the stabilization of I-jB, the cytoplasmic inhibitor
complexed to NF-jB. The stabilization of I-jB is due to the
inhibition of I-jB phosphorylation by IKKα, and results in
the cytoplasmic sequestration of p65, a major components
of the NF-jB complex ([56]; see notes added in proof (2)).
In addition, VIP/PACAP promotes CREB phosphorylation
through the cAMP/PKA pathway, and phosphorylated
CREB translocates to the nucleus where it competes for the
coactivator CBP (CREB-binding protein). CBP, found in
Figure 1. Inhibition of IRF-1 expression by VIP and PACAP.
VIP and PACAP bind to the VPAC1 receptor on macrophages
and activate the cAMP/PKA pathway. IFN-γ initiates the Jak1/
2-STAT1 pathway resulting in the generation of phosphorylated
STAT1 dimers, their translocation to the nucleus and subsequent
binding to the GAS site in the IRF-1 promoter. VIP and PACAP
prevent IRF-1 transcription by inhibiting the phosphorylation of
Jak1/2 and STAT1. The intermediary between PKA and Jak1/2
phosphorylation is not known. SOCS1 and 3 do not participate in
this process [58].
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Ganea and Delgado
Figure 2. VIP and PACAP affect the function and/or expression
of Jun family members. VIP and PACAP bind to the VPAC1
receptor on macrophages and activate the cAMP/PKA pathway.
LPS activates the MEKK1/MEK4/JNK mitogen-activated kinase
pathway leading to the phosphorylation of c-Jun, and subsequent
activation as a transcriptional factor. VIP and PACAP inhibit the
MEKK1/MEK4/JNK pathway and c-Jun phosphorylation. In
addition, VIP and PACAP activate JunB through the cAMP/
PKA pathway. Replacement of c-Jun with JunB leads to an
inactive transcriptional complex for many of the macrophagederived cytokines [59].
limiting amounts in the nucleus, is necessary for the stabilization of a transcriptionally active complex through interactions with several DNA bound transcriptional factors
(figure 3). Removal of CBP by CREB prevents the transcriptional complex from acquiring the ‘transcriptionally active’
conformation. Finally, VIP/PACAP also affect the phosphorylation of TBP (the TATA-box binding protein) through the
inhibition of the MEKK1/MEK3/6/p38 MAPK pathway (see
notes added in proof (2)). In the absence of phosphorylated TBP there is an inefficient recruitment of the RNA
polymerase II, which further weakens transcription.
Although cAMP-inducing agents mimic several of the
VIP/PACAP effects, the fact that these two neuropeptides
act through both cAMP-dependent and cAMPindependent pathways allows them to function as
extremely efficient immunomodulators.
4. Conclusions
Through their participation in both innate and adaptive
immunity, macrophages play a crucial role in the defense
against pathogens. Macrophage development and activaMicrobes and Infection
2001, 141-147
Inhibitory receptors of mononuclear phagocytes
Forum in Immunology
Notes added in proof
(1) Delgado M., Ganea D., Is vasoactive intestinal peptide a type
2 cytokine? J. Immunol. (2001) in press.
(2) Delgado M., Ganea D., Vasoactive intestinal peptide and
pituitary adenylate cyclase-activating polypeptide inhibit nuclear
factor jB-dependent gene activation at multiple levels in the
human monocytic cell line THP-1, J. Biol. Chem. 276 (2001)
369–380.
References
Figure 3. VIP and PACAP affect NF-jB transcriptional activity
at multiple levels. VIP and PACAP bind to the VPAC1 receptor
on macrophages and activate both the cAMP/PKA pathway, and
a cAMP-independent pathway. The cAMP-independent pathway
stabilizes I-jB by inhibiting the kinase activity of IKKα. The
stabilized I-jB sequesters the p65/p50 complexes in the cytoplasm. This results in a decreased NF-jB binding to promoters.
The cAMP-dependent pathway phosphorylates CREB, leading to
its nuclear translocation and subsequent binding to CBP. In the
absence of the coactivator CBP, the transcriptional complexes are
not fully active. In addition, by inhibiting the MEKK1/MEK3/
6/p38 pathway, VIP and PACAP reduce the phosphorylation of
TBP (the TATA-box binding protein) resulting in a reduced
recruitment of RNA polymerase II.
tion is controlled at various levels. Although signals from
pathogens and immune cells are the classical regulators of
macrophage activity, the nervous system and its products
represent another important level of control. Neuropeptides, released either from innervation or from immune
cells, act as stimulators or inhibitors of macrophage activity. Here we reviewed the neuropeptides with inhibitory
activities, and focused on their receptors and, where
known, on the transduction pathways and the affected
transcriptional factors. Upon release in vivo in an inflammatory milieu, the inhibitory neuropeptides inactivate the
stimulated macrophages, counteracting the proinflammatory signals. This is an important regulatory event, since
the unchecked activation of immune cells, particularly
macrophages, leads to significant tissue damage, and in
extreme circumstances to organ failure and death. Therefore, inhibitory neuropeptides play an important role in
re-establishing immune homeostasis, and represent potential therapeutic agents particularly in inflammatory and
autoimmune diseases.
Microbes and Infection
2001, 141-147
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