VIP and PACAP

10 Pages·2000·0.13 MB·English

by  Goetzl E.J., Voice J.K., Dorsam G.

VIP and PACAP
Edward J. Goetzl*, Julia K. Voice and Glenn Dorsam
Immunology and Allergy, University of California, San Francisco, 533 Parnassus Avenue,
Room UB8B, Box 0711, San Francisco, CA 94143-0711, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.13003.
SUMMARY BACKGROUND
Vasoactive intestinal peptide (VIP) and pituitary VIP and PACAP are constituents of one structural
adenylyl cyclase-activating peptide (PACAP) are superfamily of neuroendocrine hormones which also
homologous mediators that are released from cholin- includes secretin, glucagon, glucagon-like peptide,
ergic, nonadrenergic noncholinergic, and other neu- and growth hormone-releasing hormone (Table 1)
rons.Theyarerecognizedbymembersofasubfamily (SaidandMutt,1988).VIPandPACAParelinkedby
of G protein-coupled receptors. VIP and PACAP are some functional similarities based on their sharing of
distributed widely, but with anatomical peaks, in the two of the three G protein-coupled cellular receptors
nervous and endocrine systems, lungs, intestines, and in one subset.
immune organs. Their early appearance in embryo-
genesisandthedeleteriouseffectsofpharmacological
Discovery
antagonism in utero both suggest that VIP and
PACAP are critical mediators of development. In
adult mammals, VIP and PACAP normally have VIP was first identified as a potent vasodilator in
potent neural, endocrine, other physiological, and extracts of porcine intestine (Said and Mutt, 1970)
immune effects and potential pathological roles in and was subsequently found to be a 28 amino acid
esophageal achalasia, Hirschsprung’s disease of the neuroendocrine peptide distributed widely in the
colon, cystic fibrosis, diabetes, and asthma. nervous, endocrine, gastrointestinal, respiratory, and
Table 1 Structures, determinants of expression, and cellular sources of VIP, PACAP38, and PACAP27
Peptide Amino acid sequence: Regulation of expression Sources
signature structures
VIP H-S-D-A-V-F-T-D-N-Y-T-R-L-R-K- Cyclic AMP, Ca2+, NS, endo, GI, resp, and
Q-M-A-V-K-K-Y-L-N-S-I-L-N-NH neuropoietic cytokines immune systems
2
Human, pig, cow, dog
(cid:11) helix(cid:136)aa 13–20/26
PACAP38 H-S-D-G-I-F-T-D-S-Y-S-R-Y-R-K- CNS, endo, GU, GI, and
Q-M-A-V-K-K-Y-L-A-A-V-L-G-K-R- resp systems
Y-K-Q-R-V-K-N-K-NH
2
Human, ovine, rat
PACAP27 H-S-D-G-I-F-T-D-S-Y-S-R-Y-R-K-Q-M-A-
V-K-K-Y-L-A-A-V-L-NH
2
NS,nervoussystem;CNS,centralnervoussystem;endo,endocrine;GI,gastrointestinal;GU,genitourinary;resp,respiratory.
1398 Edward J. Goetzl, Julia K. Voice and Glenn Dorsam
immune systems of mammals (Said and Mutt, 1972). and several members of the neuropoietic family of
PreproVIP,theprecursorcleavedtoyieldVIP,isalso cytokines (Table 3) (Yamagami et al., 1988; Fink
the source of biologically active peptide histidine etal.,1991).The6.9kbgeneencodingpreproPACAP
isoleucine (PHI) or peptide histidine methionine is located in rat chromosome 9 and human chromo-
(PHM), depending on which species is the source, some 18p11 (Hosoya et al., 1992; Cai et al., 1995).
and a peptide histidine valine (PHV), which is a C-
terminally extended form of PHI and PHM. PACAP Regulatory sites and corresponding
was first found in extracts of ovine hypothalamus as
transcription factors
a potent stimulus of adenylyl cyclase activity in rat
culturedanteriorpituitarycells,andwassubsequently
determined to consist of one predominant 38 amino Neural cell-specific full expression of the preproVIP
acid peptide (Miyata et al., 1989) and a C-terminally gene is mediated by a tissue-specific element (TSE)
truncated 27 amino acid variant (Table 1) (Miyata consisting of a 425bp domain with two AT-rich
et al., 1990). PACAP was detected most prominently octamer-like sequences between (cid:255)4.7 and (cid:255)4.2kb
in the central nervous system, with highest concen- upstream of the transcription start site (Hahm and
trations in the hypothalamus, substantial levels in Eiden, 1998). The TSE interacts with four additional
testis and adrenal medulla, and lower levels in other promoter proximal domains defined by mutational
areas of the central nervous system, ovary, lung, eye, analyses in human neuroblastoma cell lines, includ-
intestines, and pancreas. ing a 17bp cyclic AMP-responsive element (CRE)
enhancer immediately proximal to the TSE and a
serieswithin(cid:255)1.55kbofthestartsitecomposedofan
Structure
enhancer with E-boxes and MEF2-like motifs ((cid:255)1.55
to (cid:255)1.37kb), a repressor STAT motif ((cid:255)1.37 to
VIP, PACAP38, and PACAP27 are linear peptides (cid:255)1.28kb), and an enhancer AP-1-binding sequence
with a C-terminal amide and without any complex ((cid:255)1.28 to (cid:255)0.9kb). Phorbol esters use distinct mes-
substituents (Table 1). senger pathways but trans-acting proteins of similar
DNA-binding specificity to regulate the VIP pre-
cursor protein gene convergently through the CRE
Main activities and
enhancer(Finket al., 1991).Ca2+-mediatedincreases
pathophysiological roles in preproVIP mRNA levels in human neuroblastoma
cell lines contrast with those evoked by cAMP in
being cAMP-independent, slower in time course
VIP and PACAP are potent mediators of neural
and requiring de novo protein synthesis. Although
developmentandsurvival,hormonesecretion,smooth
increases in Ca2+ induce differential rises in several
muscle function, glandular secretion, and cellular
transcription factors relative to cAMP, no promoter
migration,adhesion,andproductionofcytokinesand
element was unequivocally coupled to the effects of
other proteins (Table 2).
Ca2+. The 180kb neuropoietic cytokine response ele-
ment (CyRE) is located between the first of the three
TSE-interactive domains and the CRE in the same
GENE AND GENE REGULATION
neuroblastoma cell lines. Coordinated binding of the
STAT1 and STAT3 proteins to one CyRE site and a
Accession numbers
complex of c-Fos, JunB and JunD to an AP-1 site of
the CyRE stimulates cytokine- and cell type-specific
Human VIP: M33027, M37460, M54930, M38563, transcription of the preproVIP gene (Symes et al.,
M36634 1997). Little specific information is available about
Human PACAP: E02721, E02722 transcriptional control of the gene encoding the
Rat PACAP: E02724 PACAP precursor protein.
Cells and tissues that express
Chromosome location
the gene
The 8.8kb gene encoding preproVIP has been local-
izedinhumanchromosome6p24(Table3).Expression The genes encoding preproVIP and preproPACAP
of preproVIP is regulated with cell type specificity by arewidelyexpressedinmanytypesofcellsandtissues
intracellular cyclic AMP and Ca2+, phorbol esters, (Table 1).
VIP and PACAP 1399
Table 2 Effects of VIP, PACAP38, and PACAP27 on cellular and tissue differentiation, organogenesis, survival, and
functions
Peptide Target cell/tissue/system Effects on development and functions
Neural
PACAP Neural tube (NT), murine Patterning
VIP CNS, murine Post-NT closure early neurogenesis
VIP CNS, murine Neuronal survival, excitotoxin
resistance
PACAP NS Neurite outgrowth
VIP/PACAP CNS Neuronal proliferation,
differentiation
VIP Cerebral astrocytes, rat IL-6 generation
Endocrine
VIP Adrenal gland Production/secretion, many hormones
PACAP/VIP Rodent GI Secretin secretion
PACAP/VIP Rat GI Serotonin release
PACAP/VIP Rodent pancreas Insulin secretion
Non-neuroendocrine physiological
VIP Guinea pig, rat, human Smooth muscle relaxation
PACAP Rat, opossum Smooth muscle relaxation
VIP Rat, dog, hamster Vasodilatation, reversal of
vasoconstriction
VIP/PACAP Cat, ferret, dog, human Water and mucus secretion
VIP Rat small intestine Inhibition of transport
PACAP Rat Catecholamine secretion
Immune and inflammatory
VIP Human/mouse T cells Enhancement of adhesion
Stimulation of migration
Activation of matrix
metalloproteinases
VIP Human/mouse T+ B cells Decreased generation of IgG,
increased production of IgE, IgA
VIP Human/mouse T cells Decreased IL-2, IL-4, IL-10,
and IL-13
Increased IL-5, IFN(cid:13)
VIP/PACAP Mouse/human macrophages Induction of chemotaxis
Inhibition of TNF(cid:11) generation and
secretion
VIP Rodent mast cells Inhibition of histamine release
Elicitation of mediator release
VIP Human blood mononuclear leukocytes Inhibition of NK activity
VIP Human skin Adhesive protein expression
by leukocytes
Leukocyte infiltration
1400 Edward J. Goetzl, Julia K. Voice and Glenn Dorsam
Table3 Chromosomallocationandgenomicorganization and immune proteases frequently cleave VIP rapidly
of VIP and PACAP genes on the carboxyl-side of Asp3, Thr7, Tyr10, Tyr22,
Ser25, as well as the expected tryptic sites, and a
Peptide Species Chromosome and other monoclonal catalytic anti-VIP antibody cleaves on
genomic characteristics
the carboxyl side of Lys20, but none acts in the
predicted (cid:11) helical domain. Extensive studies of the
PACAP Rat 9
binding and functional activities of a wide range of
Human 18p11
linear and cyclical analogs of VIP have established a
VIP Human 6p24 model pharmacophore, which requires the entire
native sequence for optimum potency and is highly
dependent on Asp3, Phe6, Thr7, Tyr10, Tyr22, and
Leu23 (O’Donnell et al., 1991). Far less is known of
Figure 1 Amino acid sequences for VIP,
the structural determinants of activity of PACAP.
PACAP38, and PACAP27.
VIP
HSDAVFTDNY TRLRKQMAVK KYLNSILN CELLULAR SOURCES AND
PACAP38 TISSUE EXPRESSION
HSDGIFTDSY SRYRKQMAVK KYLAAVLGKRYKQRVKNK
PACAP27 Cellular sources that produce
HSDGIFTDSY SRYRKQMAVK KYLAAVL
VIP is distributed widely in the nervous, endocrine,
PROTEIN gastrointestinal, respiratory, and immune systems of
mammals (Said and Mutt, 1972). PACAP is present
Sequence at highest levels in the central nervous system, but
there are also substantial levels in testis and adrenal
medulla,andlowerlevelsinotherareasofthenervous
See Figure 1.
system,ovary,lung,eye,intestines,andpancreas.VIP
andPACAParebothfoundprincipallyinneuronsof
Description of protein the cholinergic and nonadrenergic noncholinergic
systems of the CNS and peripheral nerves, as well as
intrinsic neural networks of the endocrine, reproduc-
The conformation of VIP and biologically active
tive, gastrointestinal, immune, and respiratory sys-
fragments of VIP have been analyzed by physico-
tems (Said and Mutt, 1988) (Table 1). Some tumor
chemical studies, computational methods, and sus-
cells produce and store these neuropeptides, perhaps
ceptibility to peptidolysis (Haghjoo et al., 1996;
asamanifestationofdedifferentiation,butthereisno
Filizola et al., 1997). Circular dichroism (CD) esti-
apparent relationship to tumor biology. Mast cells,
mates of the secondary structure of an analog of
basophils, eosinophils, macrophages, and T cells
VIP1-28 and of various substituents of VIP1-28 in
may also contain low levels of immunoreactive VIP,
methanolic aqueous solutions showed helical content
butalargefractionofVIPinimmunecellsconsistsof
of 60–70% and suggested an (cid:11) helical domain span-
truncated or otherwise altered variants with lower
ning amino acids 13–20. However, the CD spectra in
potencyandlessactivitythanintactVIP1-28(Wershil
aqueous buffer resembled random coils with only
et al., 1993). VIP and PACAP are both expressed at
approximately 25% (cid:11) helix. The results of proton
levels predominantly determined by the balance
NMR studies of the same VIP structures in
between transcriptionally regulated synthesis and
methanolic aqueous solutions were consistent with a
susceptibilitytopeptidolysis,andexertmanydifferent
singleextended(cid:11)helixfromaminoacids11to27and
types of effects in numerous organ systems.
with the tendency to form (cid:12) turns at the N-terminus.
Calculations designed to predict lowest energy
configurations of amino acids 1–11, when attached Eliciting and inhibitory stimuli,
to an amino acid 12–28 (cid:11) helix, suggested bent or
including exogenous and
multi-turn configurations for VIP1–11 compatible
endogenous modulators
with those proposed by NMR data. The presence of
an (cid:11) helix spanning amino acids 13–20 is also sup-
ported by the findings that different neuroendocrine See Table 1.
VIP and PACAP 1401
RECEPTOR UTILIZATION secretin and inhibited secretion of serotonin from
intrinsic plexus nerves of the rodent gastrointestinal
VIP and PACAP are specifically recognized by three tract (Chang et al., 1998). VIP and PACAP raised
distinct members of a separate subfamily of G [Ca2+]iandstimulatedreleaseofinsulinbypancreatic
protein-coupled receptors. Both forms of PACAP (cid:12) cells through several different mechanisms in vitro
bind to the PAC receptor with approximate K (Leech et al., 1995). This capability of VIP was
1 d
values of 1nM while VIP binds to PAC with much demonstrated in vivo by the findings that transgenic
1
lower affinity (K (cid:136)1mM). In addition, VPAC and overexpression of VIP in mice under control of
d 1
VPAC bind VIP and the PACAPs with similar the insulin promoter increased the pancreatic (cid:12) cell
2
affinities (K (cid:136)3–10nM), and bind secretin, GRF, content and level of secretion of VIP in association
d
and other members of this neuropeptide superfamily with enhanced secretion of insulin and improved
with much lower affinities that vary with the species glucose tolerance (Kato et al., 1994).
of origin of the VPACs. Other physiological effects of VIP and/or PACAP
result from smooth muscle and vascular activities,
and actions on transport and secretory systems
IN VITRO ACTIVITIES (Table 2). VIP and PACAP mediate vasodilatation
and relaxation of smooth muscle in several organ
systems of some species. The powerful systemic and
In vitro findings
pulmonary vasodilatory actions of neurally delivered
VIP and PACAP are endothelial cell-independent
Effects of VIP and PACAPs may be considered in
andregionallyexpressed,asexemplifiedbythegreater
four broad categories: neural; endocrine; nonneuro-
effect in proximal than peripheral pulmonary air-
endocrinephysiological,includingvascular,muscular,
ways.Nonadrenergicnoncholinergicneuralresponses,
glandular and metabolic; and immune and inflam-
that relax smooth muscles of most organs and are
matory (Table 2). The principal neural effects of VIP
the principal relaxant of human pulmonary airways,
and PACAP are regulation of proliferation and gene
are mediated and modulated by VIP, PACAP, and
expression by differentiating neurons during early
endogenous nitric oxide (NO). Although the inhib-
embryogenesis (Gressens et al., 1993; Waschek et al.,
itory role of NO has been directly established in
1998). The highest fetal tissue level of VIP was
contractions induced by electrical field stimulation
observed on embryonic day 11 in rodents when no
and cholinergic activation, a dependence on crude
VIP mRNA was detected in the tissues, which led to
probing tools such as protease degradation of neuro-
thedemonstrationthatmaternalnervesarethemajor
peptides and the lack of useful pharmacological
source (Hill et al., 1996). Pharmacological antago-
agents for VIP and PACAP has prevented unequi-
nism of VIP on embryonic days 9–11 in vivo resulted
vocal confirmation of the involvement of the neuro-
in growth retardation and microcephaly, which were
peptides. In some instances, weak antagonists of VIP
prevented by administration of exogenous VIP
andPACAPhaveattenuatedneurallymediatedrelax-
(Gressens et al., 1994). Limited results of several
ationofintestinalsmoothmuscle.Therelaxingeffects
studies have documented stimulatory effects of VIP
of VIP and PACAP are expected to be more prom-
and/or PACAP on neuronal survival, outgrowth of
inent in proximal pulmonary airways and directed to
neurites, cellular differentiation, and generation of
cholinergic mechanisms, as VIPergic nerves are con-
cytokines in vitro (Said and Mutt, 1988). VIP and
centratedaroundairwayganglia.Themechanismsby
PACAP also modulate release of neuropeptides from
which VIP and PACAP relax smooth muscle have
some sensory nerves (Said and Mutt, 1988).
been only partially elucidated, but include changes
Endocrine effects of VIP are predominantly in L-type Ca2+ channel currents mediated by cAMP-
directed at regulation of secretion of numerous hor-
dependentproteinkinaseandproteinkinaseC(Leech
mones. VIP enhanced secretion of cortisol, aldoste-
et al.,1995).
rone, and androgens by cultured mixtures of human
The dense networks of VIP- and PACAP-contain-
adrenalcorticalandchromaffincells(Bornsteinetal.,
ing nerves around many different types of secretory
1999). That (cid:12)-adrenergic antagonists blocked aug-
epithelial cells and submucosal glands suggested a
mentation of corticosteroid production by VIP
role in regulating fluid and mucus production. In
suggested that a major primary effect of VIP is
many model systems, VIP and PACAP stimulate
induction of catecholamine generation by medullary
glandularsecretion,aswouldbeexpectedforadenylyl
cells.Thispossibilitywassupportedbydirectfindings
cyclase agonists, and often show preferential effects
ofVIPenhancementofadrenalcatecholaminerelease
on one component of the process. For example, VIP
(Przywara et al., 1996). VIP stimulated release of
stimulates secretion of mucus glycoproteins more
1402 Edward J. Goetzl, Julia K. Voice and Glenn Dorsam
than chloride transport or water secretion in pul- and secretion of IL-2, IL-4, IL-10, and IL-13 by
monary airways, but has greater enhancing activity transcriptional and posttranslational mechanisms
for serous than mucus secretions in nasal mucosa (Ganea and Sun, 1993; Sun and Ganea, 1993). In
(Barnes et al., 1991). Other effects on secretion and somesubsetsofmouseTcells,VIPenhancesantigen-
transport include induction of catecholamine release induced secretion of IL-5 (Mathew et al., 1992).
from adrenal chromaffin cells (Przywara et al., 1996) Similarly, IFN(cid:13) production by antigen-challenged
and inhibition of alanine absorption by the jejunum cloned and purified mouse TH1 cells is augmented
(Barada et al., 1998). VIP affects the cystic fibrosis markedly by VIP, without an effect on IFN(cid:13) pro-
transmembrane conductance regulator (CFTR), duction elicited by mitogen, anti-CD3 antibody, or
defective cellular trafficking of which is the most ionophore plus phorbol ester (Jabrane-Ferrat et al.,
common cause of cystic fibrosis. Cl secretion and 1999). VIP and PACAP also regulate cytokine pro-
selective apical membrane expression of the CFTR duction by macrophages, as exemplified by inhib-
were both significantly increased by VIP at concen- ition of TNF(cid:11) generation through transcriptional
trations as low as 10nM (Lehrich et al., 1998). mechanismsdependentonbothsuppressionofNF(cid:20)B
Although high concentrations of VIP and PACAP binding and alterations in the composition of the
may affect the localization and activities of mast cells CRE-binding complex (Delgado et al., 1998).
and inflammatory leukocytes in vitro, concentrations Third, T cell-dependent generation of IgG and, in
attainable in vivo will rarely initiate or influence somecircumstancesIgM, is inhibited morethan 90%
inflammatory or hypersensitivity reactions directly. by VIP, that concurrently enhances production of
The principal immunological and inflammatory IgA and IgE (Goetzl et al., 1990; Boirivant et al.,
effects of VIP are T cell-dependent (Table 2). Less 1994). A maximal effect depends on maintenance of
is known of the actions of PACAP on T cells and the level of VIP by repeated introduction into the
mostpreliminaryanalyseshaveshownlessbindingby culture medium.
T cells of PACAP than VIP. VIP alters thymocyte Effects of VIP on NK cells and B cells are not well
maturation with preferential promotion of develop- documented to date.
ment of helper T cells (Pankhaniya et al., 1998). The
results of in vitro studies have also identified three
major effects of VIP on human blood and rodent
Bioassays used
tissue T cells, and on cultured lines of T cells with
definedVIP/PCAPreceptors.First,VIPevokesTcell
VIP and PACAP are assessed by bioassays of effects
migration through basement membranes and con-
on cellular differentiation and function, secretion
nective tissues by increasing expression of adhesive
of hormones, proteins and mucous glycoproteins,
proteins, stimulating chemotaxis and inducing secre-
smooth muscle relaxation and vascular dilatation,
tion of specific matrix metalloproteinases (MMPs)
and cellular migration and adhesion (Table 2).
(Johnstonetal.,1994;Xiaetal.,1996).VIPfacilitates
interactions of T cells with endothelium and con-
nective tissues by increasing expression of P- and E-
selectins and enhancing T cell (cid:12) integrin-dependent
1
binding to VCAM-1 and fibronectin (Smith et al., IN VIVO BIOLOGICAL
1993; Johnston et al., 1994). Chemotaxis of T cells ACTIVITIES OF LIGANDS IN
through micropore filters coated with mixtures of
ANIMAL MODELS
basement membrane components is stimulated by
VIP at concentrations as low as 0.1nM and requires
Normal physiological roles
T cell secretion of MMPs-2 and -9 to create channels
in the basement membrane matrix (Xia et al., 1996).
Basement membrane transmigration of T cells stim- The results of analyses in four distinct settings
ulated by VIP, but not that elicited by some chemo- illustrate the promise of potent and distinct activities
kines,issuppressedbyMMPinhibitors.VIPinduction forVIPandPACAP,andalsodemonstratetheprob-
of all aspects of T cell migration is mediated selec- lems of obtaining unequivocally definitive results.
tively by VPAC , whereas in some subsets of T cells First, pharmacological antagonism of VIP on embry-
2
VPAC signaling inhibits migration in response to onic days 9–11 in vivo resulted in growth retardation
1
other chemotactic factors (see chapter on PACAP and microcephaly, that were prevented by admin-
and VIP Receptors). istration of exogenous VIP (Gressens et al., 1994).
Second, concentrations of VIP attained in tissues Although this finding supports the likely involve-
mountingimmuneresponsesinhibitTcellproduction ment of VIP in ontogeny, the only available
VIP and PACAP 1403
pharmacological agents employed lack potent antag- and immunochemical analyses. The lack of useful
onistic activity and possess some partial agonist invivopharmacologicalantagonistspreventedfurther
functions. definition of the immunoregulatory roles of VIP in
Second, in trials of bronchodilator activity, this model.
intratracheal VIP alone only weakly and transiently More definitive investigations of the in vivo effects
(t (cid:136)4 minutes) reversed the bronchoconstriction of VIP and PACAP will require not only the devel-
1/2
evoked in guinea pig lungs by intravenous admin- opmentofselectiveagonistsandantagonists,butalso
istration of 50mg/kg of histamine. In contrast, the of forms of delivery of the peptides that stabilize
effects of N-terminally acetylated and amino acid- active configurationsandminimizeproteolyticinacti-
substituted analogs of VIP with higher in vitro vation. One such recent effort involves the use of
potencies were greater and longer-lasting, with dura- liposomal VIP in a hamster cheek pouch model that
tions of up to 4 hours (O’Donnell et al., 1994). allows intravital microscopic evaluation of vascular
However,theseanalogsalsoincreasedbronchialblood events and in situ administration of vasoactive medi-
flow more effectively, which may have led to more ators.VIPonstericallystabilizedliposomesassumesa
efficient clearance and metabolism of the histamine. predominantly (cid:11) helical conformation. Suffusion of
Bioavailable VIP analogs also preventedthe broncho- eitherphenylephrineorangiotensinIIvasoconstricted
constriction, bronchial edema, and lung tissue eosino- hamster cheek pouch blood vessels significantly and
philic responses of sensitized guinea pigs to liposomal VIP, but not aqueous VIP, attenuated this
intratracheal antigen challenge. vasoconstriction with maximal effect at 30 minutes
Third, acute infusion of 10nmol of VIP into the after administration (Ikezaki et al., 1998). Optimal
afferent lymphatics of lymph nodes in sheep reduced concentrations of numerous other vasodilators failed
efferent flow of lymphocytes by approximately 75% to reverse phenylephrine or angiotensin II-evoked
for many hours (reviewed in Goetzl et al., 1990). VIP vasoconstriction, emphasizing the distinctive effec-
demonstrated selectivity in control of lymphocyte tiveness of liposomal VIP.
traffic, as B cells were affected more than T cells
and CD8+ T cells more than CD4+ T cells. The
Transgenic overexpression
underlying mechanisms remain obscure, however,
and oppose results of related studies. Physiologically,
increases in flow of both lymph and the blood that Transgenic upregulation of expression of VIP in
is a source for lymphatic lymphocytes after admin- pancreatic islet (cid:12) cells resulted in greater secretion of
istration of VIP would be expected to produce the insulin andimprovedglucosetoleranceinmice(Kato
opposite result. Further, the rank order of frequency et al., 1994).
of VIP receptors is CD4+ T cells >CD8+ T cells(cid:29)
Bcells,asarethemagnitudeofinvitroeffectsofVIP.
Interactions with cytokine network
Fourth, prominent effects of VIP are observed in
in vivo compartmental immune responses. VIP is
released into fluid of the anterior chamber of the eye VIPregulatesnegativelyandpositivelythegeneration
at nanomolar concentrations after local antigen chal- of cytokines by macrophages and lymphocytes.
lengeofimmunizedanimalsorintroductionofimmu-
nologically active cytokines (Taylor et al., 1994;
Ferguson et al., 1995). The capacity of this VIP to PATHOPHYSIOLOGICAL ROLES
suppressproductionofIFN(cid:13)anddelayed-typehyper-
IN NORMAL HUMANS AND
sensitivity reactions in the anterior chamber was
DISEASE STATES AND
shownbylossofsuppressionafterspecificabsorption
or antagonism of VIP. In another series of studies of DIAGNOSTIC UTILITY
neuromodulation of regional immunity, intratracheal
antigen challenge of primed mice resulted in release Role in experiments of nature
of VIP into pulmonary tissues. The concentration of
and disease states
VIP attained nanomolar levels in bronchoalveolar
lavage fluid with a peak 1–3 days after that of sub-
stance P and concurrent with the time of maximal In the absence of animals or humans with genetically
infiltration of CD4+ T cells (Kaltreider et al., 1997). determined deficiencies of VIP or PACAP, and with-
More than 50% of the CD4+ T cells responding to out antagonists having reliable bioavailability, con-
antigen expressed VPAC and/or VPAC , as assessed clusions about pathogenetic participation are based
1 2
by quantification of mRNA encoding the receptors on findings of abnormally high or low levels in
1404 Edward J. Goetzl, Julia K. Voice and Glenn Dorsam
involved tissues in relation to expression of a disease. enhancer element in the vasoactive intestinal peptide gene.
Deficiencies of VIPergic nerves, assessed by mor- J.Biol.Chem.266,3882–3887.
Ganea,D.,andSun,L.(1993).VIPdownregulatestheexpression
phometriccriteria,havebeenobservedattheaffected
ofIL-2butnotofIFN-gammafromstimulatedmurineTlym-
tissue sites of patients with esophageal achalasia and
phocytes.J.Neuroimmunol.47,147–155.
Hirschsprung’s disease of the colon, where absence Goetzl, E. J., Adelman, D. C., and Sreedharan, S. P. (1990).
of VIP may contribute to each characteristic disorder Neuroimmunology.Adv.Immunol.48,161–190.
of gastrointestinal motility (Said and Mutt, 1988; Gressens, P., Hill, J. M., Gozes, I., Fridkin, M., and
Brenneman,D.E.(1993).Growthfactorfunctionofvasoactive
reviewed in Goetzl et al., 1990). Similarly, subsets of
intestinal peptide in whole cultured mouse embryos. Nature
patientswithcysticfibrosisorasthmahavediminished
(Lond.).362,155–158.
respiratory airway content of VIP, that may account Gressens,P.,Hill,J.M.,Paindaveine,B.,Gozes,I.,Fridkin,M.,
in part for the respective abnormalities of exocrine andBrenneman,D.E.(1994).Severemicrocephalyinducedby
secretion and bronchial reactivity (Said and Mutt, blockadeofvasoactiveintestinalpeptidefunctionintheprimi-
tive neuroepithelium of the mouse. J. Clin. Invest. 94, 2020–
1988; Goetzl et al., 1990). Other reductions in tissue
2027.
content of VIP observed transiently in acute inflam-
Haghjoo, K., Cash, P. W., Farid, R. S., Komisaruk, B. R.,
matory or metabolic illnesses have been attributed to Jordan, F., and Pochapsky, S. S. (1996). Solution structure of
cytokine- or drug-induced reductions in synthesis, vasoactiveintestinalpolypeptide(11–28)-NH ,afragmentwith
2
accelerated biodegradation, and/or increased use analgesicproperties.PeptideRes.9,327–331.
Hahm, S. H., and Eiden, L. E. (1998). Five discrete cis-active
through binding to greater numbers of cellular
domainsdirectcelltype-specifictranscriptionofthevasoactive
receptors.
intestinalpeptide(VIP)gene.J.Biol.Chem.273,17086–17094.
Hill, J. M., McCune, S. K., Alvero, R. J., Glazner, G. W.,
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LICENSED PRODUCTS
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wall of a vasoactive octacosapeptide related to secretin and
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VIP cyclic analog agonists (Astra, Stockholm from
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Hoffman LaRoche, Inc.)
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