The biochemical coding of the stress response
has been unraveled in the past decades through the identification of a 41-amino
acid peptide, corticotropin releasing factor (CRF), and its related peptides,
urocortin 1 (Ucn 1), Ucn 2 and Ucn 3. CRF and urocortins exert their biological
actions by interacting with CRF
1 and CRF
2 receptors,
encoded by two distinct genes (1-3). In particular, CRF plays a crucial role
in the stress-related stimulation of the hypothalamo-pituitary-adrenal axis
through activation of pituitary CRF
1 receptor and, in association with urocortins,
acts as a neuromodulator to coordinate the behavioral, autonomic, and visceral
efferent limbs of the stress response (1-4).
The gastrointestinal (GI) tract is particularly sensitive to stress. Convergent
preclinical evidence has accumulated over the years suggesting that stress-related
alterations of GI functions, particularly at the colonic level, are primarily
mediated by the activation of brain CRF/CRF
1
signaling (2, 5). However, recent studies point to an equally important contribution
of the peripheral CRF signaling locally expressed in the gut to the GI stress
response (6-11). In addition, there is increasing experimental and clinical
evidence that the induction and progression of inflammatory and functional intestinal
disorders are influenced by CRF signaling pathways (12-14). Among the inflammatory
bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), share
many clinical features, but also important differences, such as disease location
and histological features (13). CD is a chronic transmural inflammatory disease
affecting the terminal ileum and the colon, which is associated with frequent
attacks of diarrhea, abdominal pain, nausea and fever, while UC affects primarily
the distal colon. Irritable bowel syndrome (IBS) is a highly prevalent functional
GI disorder affecting predominantly the colon which is mainly characterized
by abdominal pain and discomfort in association with altered bowel habits in
the absence of any structural abnormalities (15). Despite differences in their
etiologies (16, 17), stress represents a common risk factor in the pathogenesis
of IBS and IBD (14, 18, 19). In this review, we will summarize evidence in support
of a major role for peripheral CRF signaling in the GI stress response in both
humans and rodents, with a special emphasis on the colon and the ileum, and
we will discuss the relevance of these preclinical findings in relation with
components of stress-related impact on IBS and IBD.
CRF SIGNALING SYSTEM OVERVIEW
Both CRF
1 and CRF
2
receptors are members of the G-protein coupled receptors family. In most cells
in the peripheral tissues, the physiological actions of CRF and urocortins involve
coupling of both CRF
1 and CRF
2
receptors to G
s
proteins that stimulate cAMP mediated signaling cascades (20). However, couplings
to other types of G proteins have also been described (21). The activation of
cellular G-protein after CRF receptor stimulation leads to the induction of
multiple signaling pathways (MAPK, PK, ERK1/2), which differentially influence
neuronal, endothelial, endocrine, smooth muscle, epithelial and immune cell
activities (21-24). These differential effects depend on a number of factors
including the subtype of CRF receptor activated, the tissue in which the activation
occurs and environmental factors. Although CRF
1
and CRF
2 share about 70% amino acid identity,
they exhibit differential pharmacologies due to their distinct N-terminal ligand
binding domains (20). Hence, CRF binds with the highest affinity to CRF
1
receptors (20) while Ucn 1 shows an equal high affinity to both CRF receptor
types and Ucn 2 and Ucn 3 are selective agonists for CRF
2
receptors (20). Several splice variants of CRF receptors have been identified
in rodents and humans: CRF
1 (
,
ß, c-n) of which only CRF
1a is functional
(21), while both CRF
2
and CRF
2ß are functional (20, 21, 25).
In rodents the predominant form expressed in the periphery is CRF
2ß
(26), although several CRF
2
isoforms have recently been isolated in the esophagus (25).
It is traditionally accepted that CRF, Ucn 1 and Ucn 2 bioactivities are modulated
by binding to the secreted CRF binding protein (CRF-BP) (27, 28). However, additional
regulatory pathways have been recently unveiled. The CRF
1
alternative splice variants, for instance, contain truncation and/or deletions
that disrupt ligand binding and/or signaling capabilities of functional CRF
1
receptors, subsequently affecting CRF and/or urocortins effects in target tissues
(25, 29). A soluble CRF
2
protein was also identified in mouse brain and rat esophagus and initially thought
to behave as a binding protein (30). However, subsequent studies found that
despite its correct translation, this protein is not secreted and may therefore
alter the transcription of full-length CRF
2
mRNA in cells, instead of acting as a decoy receptor (25, 31). Furthermore,
in the mouse heart, a dominant-negative CRF
2ß
splice variant (i.v.-mCRF
2ß),
recently described, was shown to impair mCRF
2ß
function by retaining its cellular location to the endoplasmic reticulum-Golgi
complex (32). Together these studies demonstrate that the CRF signaling system
is finely tuned by a number of regulatory pathways at the receptors and the
ligands levels.
DISTRIBUTION OF CRF LIGANDS AND RECEPTORS
IN COLON AND ILEUM: REGULATION BY STRESS
In contrast to the brain, where it has been extensively described, the distribution, expression pattern and regulation of CRF receptors and ligands in the GI tract of mammals is still incomplete. In this section we will focus on what is known in humans and rodents (mouse, rat, guinea-pig) at the colonic and ileal levels.
Expression of CRF receptors in the colon
Both CRF receptors subtypes have been detected at the gene and/or protein level
in humans and rodent colons (
Table 1). We recently described the expression
of CRF
1 mRNA in colonic resections from healthy
adults and the presence of CRF
1 immunoreactivity
(IR) in lamina propria (LP) cells which were identified by immunohistochemistry
as being macrophages and mast cells, as well as in submucosal (SNP) and myenteric
neuronal plexus (MNP) (33). This supports earlier data in human colonic resections
showing gene expression of CRF
1, CRF
2
and to a minor extent CRF
2ß in isolated lamina
propria mononuclear cells (LPMCs), as well as very little CRF
2
mRNA in epithelial cells fractions (34). The low gene expression of CRF
2
receptors in healthy human colonic epithelium found in this study is in agreement
with recent reports showing little or even no expression in a number of transformed
or non-transformed human colonic cell lines (Caco-2, HT-29, NCM460) as well
as in human colonic biopsies or xenografts (35, 36). Interestingly, at the protein
level, CRF
2 IR has been detected, although weakly,
in healthy human colonic epithelial cells (35), and with much higher intensity
in LPMCs, SNP, MNP, vascular endothelial cells and vascular smooth muscle cells
of blood vessels (37). CRF
1 and CRF
2
receptors were also identified at the gene and protein level in BON cells, a
pancreatic carcinoid-derived human endocrine cell line, which share functional
similarities with intestinal enterochromaffin cells (36) and in mast cells in
sigmoid colon biopsies and in HMC-1 cells, a human mast cell line (38). In rats,
CRF
1 mRNA was mainly found in MNP, SNP, goblet
cells and stem cells of the colonic crypts as well as in scattered cells of
the surface epithelium and the lamina propria of the proximal colonic mucosa
(26, 39, 40). In contrast, CRF
2 expression was
essentially detected in the mucosa, localized in the luminal surface of the
crypts and in blood vessels of the submucosal layer (40). Immunoreactivity for
CRF
1 has been detected in guinea-pigs’ colonic
MNP and SNP, while CRF
2 IR was only detected
in MNP (41, 42).
Table 1. Distribution
of CRF receptors and ligands (mRNA and immunoreactivity) in human and
rodent colon and ileum. SNP: submucosal neuronal plexus, MNP: myenteric
neuronal plexus, VEC: vascular endothelial cells, VSMC: vascular smooth
muscle cells, SML: smooth muscle layer, LP: lamina propria, ND: non determined. |
|
Expression of CRF ligands in the colon
Most of the studies assessing the distribution of CRF and its related peptides in the colon show that they are expressed in close proximity of the CRF receptors, pointing out the existence of local autocrine/paracrine regulatory loops. For instance, in humans, CRF mRNA was found in the mucosa, mainly localized in enterochromaffin cells (43). In contrast, Ucn 1 IR and mRNA were detected in colonic lamina propria macrophages with a minimal amount in epithelial cells (34). Ucn 3 mRNA and IR were found in the MNP and SNP, in subserosal vascular endothelial and smooth muscle cells, in colonic smooth muscle layers and in enterochromaffin cells of human colonic tissue, as well as in enteric glial cells (37). As of today, the presence of Ucn 2 in human colon has not been described.
In rats, we recently showed that CRF is expressed in the colon, predominantly in the distal part, with the highest levels of expression in the submucosal plus muscle layers compared to the mucosa (44). CRF IR was detected in individual cells scattered in the mucosa, mainly located in enterochromaffin cells, cells in the crypts and LP, as well as in MNP (33). In earlier studies, the preproCRF IR labeling was detected in rat colonocytes, with weaker detection in colonic bottom crypts and submucosal cells (10). CRF IR was found in MNP and SNP in all segments of the large intestine of guinea-pigs, although CRF IR positive cells were sparse (45). Along with CRF, Ucn 1 mRNA and IR was observed in rat MNP and SNP (46, 47). Of note, in the guinea-pig colon, CRF positive neurons do not bear CRF
1 receptors but the CRF
1 positive neurons are expressed in neuronal neighbors (45). In the rat colon, Ucn 1-positive neurons are co-localized with CRF
1 receptor positive neurons (46). Ucn 2 mRNA was also detected throughout the large intestine of rats in the MNP and the nerve fibers innervating the circular muscle (48). With regards to the peptide, Ucn 2 IR was measurable in all layers of the rat intestinal tract, including the mucosal and submucosal layers, and detected in epithelial cells of the mucosa, as well as in support cells and immune cells of the LP, SNP, MNP (48). Taken together, these data suggest that the colon in humans, rats and guinea-pigs is an important target organ for CRF signaling.
Table 2. Effects
of peripheral CRF1 or CRF2
receptor signaling on motility, secretion, permeability, inflammation
and pain perception in colon and ileum.
Peripheral CRF signaling activation increases measured activation state;
Peripheral
CRF signaling decreases measured activation state; ? No direct reports
about peripheral CRF signaling effects on mentioned functional system
in the specific gut segment |
|
Expression of CRF receptors and ligands in the ileum
Conversely to the colon, the ileal distribution and expression of CRF receptors and ligands have been little investigated in rodents and there are no data in humans, yet. In rats and guinea-pigs, CRF
1 and CRF
2 IR were detected in MNP and SNP (45, 49), as well as in nerve fibers of the longitudinal and circular muscle layers and in mucosal cells of the ileum (49). In mice, CRF
1 mRNA was detected in ileal LP and epithelial cells, while CRF
2 mRNA was only found in a few cells of LP (50).
While the expression of urocortins in the ileum has not been investigated, CRF IR was found to be sparsely distributed in MNP and SNP of the guinea-pig ileum (45). In rats as well, CRF IR was detected in ileal SNP and in LP immune cells and Paneth cells, but not in epithelial cells (51). Lastly, in mice ileum, CRF IR was primarily present in subepithelial cells and a few cells of the epithelial surface (50). Hence, although not extensively studied thus far, the ileum appears to be a potential target for CRF/Ucn signaling.
Regulation of colonic and ileal CRF receptors and ligands expression by stress
While convergent functional evidence accumulates in favor of a major role of
peripheral CRF signaling system in the GI stress response, details on how and
where the peripheral CRF signaling is recruited by stress still remains unclear.
Several recent reports suggest that stress of either interoceptive (infection,
inflammation) or exteroceptive (psychological or physical stress) origin can,
as it has been shown in the brain, affect the expression of CRF signaling in
the GI tract. In human, exposure to
Clostridium difficile toxin A was
reported to increase the expression of CRF
2
mRNA and IR in HT-29 colonocytes and colonic xenografts (35). Similar upregulations
in response to
Clostridium difficile toxin A perfusion in an ileal loop
were observed in mice for CRF
1 and CRF
2
mRNA (50, 52) and CRF mRNA in both rats and mice (50, 51). Colonic inflammation
induced by trinitrobenzene sulfonic acid in rats also increased Ucn 2 expression
in a large population of infiltrating immune cells (macrophages) (48). In our
own studies, we found that rat colonic CRF mRNA was upregulated in response
to an intraperitoneal injection of lipopolysaccharide (LPS) (44).
Differential expression of peripheral CRF signaling could also be the cause of higher or lower susceptibility to stress in individuals. In support of this hypothesis, Wistar Kyoto and Sprague-Dawley, two strains of rats with diverse anxiety sensitivities, were recently reported to exhibit differential profiles of CRF
1 and CRF
2 receptor expression in their colon under basal conditions and following an acute stress such as colorectal distension (CRD) or exposure to an open field (53). These results open new venues of investigation, particularly in light of the recent description of alternative splice variants for both receptors (21, 25).
ROLE OF CRF SIGNALING PATHWAYS IN THE COLONIC
AND ILEAL RESPONSES TO STRESS
Propulsive motor function
When injected peripherally, CRF strongly alters colonic motility and transit in several mammalian species including rodents and humans (2). Clinical studies show that systemic injection of CRF induces a colonic motility response that includes the occurrence of clustered contractions in the descending and sigmoid colon, which is more prominent in IBS patients than in healthy controls (54). In rat colon, peripheral injection of CRF and Ucn 1 increases clustered spike-burst propagative activity (55, 56) and stimulates distal colonic transit and defecation (55, 57, 58). Similarly to peripheral CRF injections, acute physical or psychological stress in humans increases colonic propulsive motor function (59-62) although in other studies, increase or no change have been reported (63-65). In rodents, acute stress (restraint, water avoidance stress (WAS)) has been clearly established to stimulate colonic transit and defecation (for review see (2)). In contrast to the colon, very little is known about the effect of peripheral CRF or stress on the ileum in humans. In rodents, only a few studies have specifically focused on the ileum and all show an inhibitory effect of stress on ileal contractility (66-68). Convergent studies to characterize the CRF receptors involved in these processes have established that the stimulation of colonic motility after peripheral administration of CRF and Ucn 1 involves CRF
1 receptors in rats and mice (2), while in contrast the inhibition of ileal phasic contractions involves activation of CRF
2 receptors in rats (49, 51).
At the colonic level, the stimulation of motility and transit induced by peripheral
CRF injection in conscious rodents is not affected by ganglion blockade, suggesting
that the effects are peripherally mediated (69). Similarly, the functionality
of the peripheral CRF signaling system in the colon during stress is supported
by reports that peripherally injected peptide antagonists which do not cross
the blood-brain-barrier, namely a-helical CRF
9-41
or astressin, block or blunt the stimulation of distal colonic transit and fecal
pellet output induced by acute wrap restraint or WAS in rats (55, 58, 70, 71).
Further support for a peripherally-restricted action of CRF peptide when injected
peripherally is that it can be reproduced
in vitro in colonic and ileal
preparations. In an isolated colonic rat preparation, CRF increased basal myoelectrical
peristaltic activity (55, 72) and increased phasic contractions and electric
field stimulation off-contraction in isolated colonic muscle strips (46), whereas
CRF and Ucn 1 inhibited the phasic contractions in ileal circular muscle strips
(49). In guinea-pig ileum however, CRF was found to either stimulate the circular
muscle activity in strips (73) and increase contractions in longitudinal muscle
myenteric plexus preparation (74), or to have no influence on ileal smooth muscle
strips contraction (75), highlighting possible species differences between rats
and guinea-pigs ileum response.
Convergent evidence suggest a major role of enteric neurons in the mediation
of peripheral CRF effects on colonic and ileal motility as also found for the
colonic response to acute stress (76). First, the neuronal blocker, tetrodotoxin
abolishes Ucn 1-evoked phasic contractions in colonic smooth muscle strips (46),
indicative of an enteric nervous system (ENS)-mediated event. Second, when injected
intraperitoneally in rats, CRF induces Fos expression, a marker of neuronal
activation, in cholinergic and nitrergic myenteric neurons in the colon (77).
Atropine, a muscarinic blocker, does not affect CRF-induced neuronal activation,
indicating that it is not secondary to the activation of muscarinic receptors
either on the myenteric ganglia (which possess both nicotinic and muscarinic
receptors) or on colonic muscles (77) but rather to a direct effect on enteric
neurons. In agreement with this, atropine prevents the CRF-induced ileal muscle
contractions of guinea-pig preparations confirming that CRF does not act directly
on the smooth muscle but exerts an excitatory action on the myenteric plexus
via acetylcholine release (74). Third, direct administration of CRF or
urocortins in ileal and colonic myenteric and submucosal plexus preparation
of guinea pig excites both myenteric and submucosal neurons as monitored by
electrophysiological recordings (41, 42, 78). In conscious rats, Fos expression
in colonic myenteric neurons in response to intraperitoneal CRF is prevented
by administration of the non-selective antagonist astressin and the selective
CRF
1 antagonist CP-154,526 and reproduced by
intraperitoneal injection of the selective CRF
1
agonists, stressin
1-A and cortagine suggesting
a major participation of CRF
1 receptors in these
effects (7, 39, 77). In the guinea-pig colon as well, the predominant expression
of functional CRF
1 receptors, relative to CRF
2
receptors, along with the expression of CRF
1
receptors ligands in colonic enteric neurons (45-47) suggest that CRF
1
signaling is the main modulator in the ENS (41). Interestingly, in the rat ileum,
Fos activation in response to activation of CRF
1
receptors is restricted to the submucosal enteric neurons, showing differential
modulation of ileal
vs. colonic enteric neurons by CRF ligands (39).
In the colon, CRF and Ucn 1 action on the ENS to increase the contractility
is related to the enhancement of cholinergic, nitrergic and serotonergic neurotransmission
(39, 46). To date, the effector mechanisms involved in the inhibitory effect
of CRF and Ucn 1 on rat ileum remain unknown.
Together these data support the possibility that stress-induced alterations of colonic and ileal motility are linked to the activation of the peripheral CRF signaling in enteric neurons, with excitatory effects being mediated through CRF
1 which in turn recruit the cholinergic, nitrergic and serotonergic transmission and inhibitory effects through CRF
2 receptors.
Epithelial barrier function in relation with enteroendocrine, epithelial and immune cells
The gut wall is protected by 1) a barrier composed of a single layer of polarized intestinal epithelial cells tightly sealed by tight junctions that regulate the passage of fluid, antigens and macromolecules as well as secrete mucus, antimicrobial peptides and immunoglobulins to limit bacterial colonization, and 2) a well developed immune system. A breach in the gut wall due to alterations in secretion and/or epithelial barrier physical disruption allows pathogens to get access to the lamina propria, which can in turn affect the local immune activity, participating in the onset and maintenance of intestinal diseases (79, 80).
The GI tract contains a variety of cells which participate in the innate defense mechanisms of the epithelium as well as in the control of intestinal secretory, motor and immune functions. Despite their low numbers in the GI tract, enterochromaffin cells, a subtype of enteroendocrine cells, store more than 80% of the organism’s serotonin (5-HT) (81). Enterochromaffin cells act as sensor cells that signal every luminal change (acidity, osmolarity, nutrients, pathogens, bacterially-derived toxins) by releasing 5-HT in the gut (81, 82). The release of 5-HT that can occur constitutively and following stimulation activates nerves fibers, which besides affecting gut motility and the sensory response, can also cause the secretion of mucus from goblet cells and an increase in passive water flux to wash away any pathogens or noxious agents (83). There is considerable evidence that peripheral release of 5-HT is involved in stress- and central CRF-mediated alterations in rodent GI functions (71, 84-90). However, the role of peripheral CRF in these effects has been little addressed. Nevertheless, two pieces of evidence point towards enterochromaffin cells being a potential direct target of the CRF signaling system peripherally. First, enterochromaffin cells in the human colon express CRF and Ucn 3 (37, 43). Second,
in vitro studies using BON cells, an enterochromaffin cell-like cell line, showed they respond to rat/human CRF and the selective CRF
2 ligand, human Ucn 3 with cAMP formation and release of serotonin (36).
Goblet cells, that are present in the ileum and the colon, secrete and release mucus in the lumen, which protects the mucosa of close bacterial interaction/penetration by forming a coating layer over the epithelium (91). The direct influence of peripheral CRF signaling activation on mucus release has not been directly assessed, however, the presence of CRF
1 receptors on goblet cells and the fact that stress and peripheral injection of CRF induces mucus depletion and reduces the number of goblet cells in rat distal colon (70, 92, 93) suggest the likelihood of a direct action of CRF or urocortins on mucin secretion (40).
The intestinal epithelium also contributes to host defense by producing antimicrobial
peptides (AMPs) (94, 95). A number of cells in the gastrointestinal tract can
secrete AMPs, including epithelial cells, mast cells or Paneth cells, specialized
cells which are located deep in the small intestine crypts (94-96). It is currently
unknown whether the peripheral CRF signaling plays any role in the release of
AMPs under conditions of stress. However, few studies in human and rodents suggest
that this innate defense mechanism can be recruited under conditions of stress
and that its defect could participate to the pathogenesis of IBD and IBS (97-101).
Thus, in women, acute cold stress was shown to induce a significant release
of
-defensin in
the jejunum (102). In mice and rats, Paneth cells’ secretory activity in the
small intestine is affected by infective and nutritional stress (103). Whether
this is also the case for psychological or physical stress is not known. Recent
data showing a decreased release of antimicrobial peptides in the skin after
a psychological stress support the possibility that stress might affect this
protective pathway in the gut as well (104).
In addition to mucosal and enteroendocrine cells, the colon and the ileum in
particular are home to a variety of resident immune cells such as mast cells,
lymphocytes, and macrophages which are known to occupy a key role in the control
of intestinal immunity, and which have been identified as targets of CRF signaling
in other organs such as the skin, lungs and brain (12). Their modulation by
peripheral CRF in the gut has been recently investigated. In a number of tissues
including the gut, mast cells have been found to express the CRF receptors (38,
105-107), and their activation by either urocortins or CRF (105) leads to the
selective release of cytokines and other pro-inflammatory mediators (108) well
established to affect the epithelial barrier function (10, 109-111). Several
studies documented that peripheral CRF affects colonic epithelial function in
human (38) and rats (112-114)
via recruitment (115) and activation of
mast cells and both CRF
1 and CRF
2
receptors (38, 112-114). The influence of CRF signaling on ileal mast cells
has been less investigated. In our recent studies, we found that in mice treated
with the selective CRF
1 agonist, cortagine,
the colon responds with increased TGF-ß expression known to be a potent
modulator of human intestinal mast cell effector functions (116). In addition,
the ileum exhibits a dose-related interferon
(IFN
)
response indicating T cell and/or natural killer (NK) cell activation, which
is followed by tight junction deregulation and dose-dependent apoptotic loss
of different cell populations (Kiank
et al, unpublished data). Thus,
in the ileum, cells other than mast cells may be responsible for CRF signaling
mediated immune stimulation. Earlier studies indicated that CRF stimulates the
proliferation of human lymphocytes by increasing interleukin (IL)-2 receptor
expression and enhancing the production of IL-1 and IL-2 (117). Thus, the intestinal
lymphocyte activation may be triggered by local CRF signaling.
Macrophages are also a target for peripheral CRF signaling
via CRF
2
receptor and may influence the mucosal immune homeostasis
via this pathway
(118). For instance, in the presence of CRF, Ucn 1 and Ucn 2, murine macrophages
were shown to transiently inhibit a LPS-induced TNF-
response, which was followed by a second phase of heightened TNF-
production (119). It was also demonstrated that low doses of Ucn 1 and Ucn 2
(10
-10-10
-8 M) enhance
macrophages apoptosis which may trigger an anti-inflammatory response whereas
high doses did not (120). Additional evidence for the anti-inflammatory effects
of peripheral CRF was demonstrated in human monocyte-derived dendritic cells,
which express both CRF
1 and CRF
2
receptors, and responded to CRF treatment with an attenuated IL-18 production
which is anti-inflammatory by promoting a Th1 shift of the T cell response (121).
Taken together, these data hint for time- and dose-dependency of CRF receptor
ligands to modulate inflammatory processes (for review see (12)).
A number of reports also suggest that stress, like CRF, can recruit and activate
mast cells (93, 122-125), neutrophils (93), eosinophils (126) and mononuclear
cells (93, 127) in the jejunal, ileal and colonic mucosa. In human jejunum,
acute pain induced by cold exposure induces mast cell degranulation (102, 128).
Compared to healthy controls, IBS patients, who present high levels of psychological
stress, exhibit higher numbers of mucosal mast cells in their jejunum (129)
and colon (130, 131), as well as CD8+ T lymphocytes in the colon (132). In mice
exposed to acute restraint combined with noise stress, the colonic mast cell
degranulation involves the over-production of IFN
(133)
and chronic restraint stress increases eosinophils expressing CRF in the jejunum,
which participate to the recruitment of mast cells and epithelial barrier dysfunction
(126). Repeated exposure of rats to WAS also induces hyperplasia and activation
of mast cells, causes an infiltration of neutrophils and mononuclear cells,
and increased myeloperoxidase activity in both the ileal and colonic mucosa
which is associated with bacterial adhesion and penetration into enterocytes
(93, 127, 134). When acute restraint stress occurred under conditions of preexistent
colonic inflammation induced by dinitrobenzene sulfonic acid, it evoked an inflammatory
relapse with significant macroscopic colonic damage, increased myeloperoxidase
activity and significant infiltration of mucosal and submucosal T cells (135).
Likewise, in mice this heightened stress-induced reactivation of experimental
colitis was shown to depend on T helper cell activation (136), suggesting recruitment
of T cells in stress conditions that may participate to intestinal inflammation.
Thus, CRF signaling can transfer stress signals to enteroendocrine, mucosal and immune cells which are resident or infiltrate the GI tract during inflammation. Mast cells, macrophages and mononuclear cells appear as likely target cells of CRF signaling (for review see (12)) which can have both, pro- and anti-inflammatory effects and may thus have damaging or protective effects on intestinal homeostasis. In addition, there seems to be a site specificity of CRF signaling effects which might be at the origin of a different stress response in the colon and ileum. Therefore, the final outcome of activation of CRF/CRF
1 or Ucn 2/CRF
2 paracrine circuit on intestinal secretory and motor function or on the inflammation appears to be highly organ/tissue-specific and context-dependent.
Ion and water secretion
The maintenance of an appropriate fluid balance, assured by ion and water secretion, is essential to the normal function of the small and large intestines. As indicated earlier, this capacity for high ion and water secretion in the intestine is a defense mechanism serving to flush out pathogens, thereby preventing mucosal adhesion, which is commonly observed as the phenomenon of diarrhea (137). Intraperitoneal CRF administration induces a watery diarrhea with rapid onset in rats (138). This diarrhea is antagonized by selective CRF
1 antagonists (138) and mimicked by a peripheral injection of the selective CRF
1 agonist, cortagine, in both rats and mice (7, 39). Similarly, restraint stress induces watery diarrhea in rats (89, 139).
Water moves passively at the epithelial level thanks to an active ion transport
assured by villus epithelial cells that are absorptive (
via sodium) and
crypt epithelial cells which are secretory (
via chloride). Changes in
this active ion transport across the tissue, or secretory response, can be measured
in vivo by the double- or triple-lumen closed-segment perfusion technique
(102, 140, 141) or
in vitro using Ussing chambers by measuring the short
circuit current (Isc). In humans, studies on intestinal secretory function have
been limited to the influence of psychological or physical stress on the jejunum,
where dichotomous listening was found to cause a reduction in net water absorption
coupled with net sodium/chloride secretion (140). Other studies showed that
acute cold stress induces a chloride-related decrease in peak secretory response
in women with moderate background stress (102). In rats, both acute intraperitoneal
administration of CRF and chronic subcutaneous administration of CRF increase
the basal colonic Isc (113, 115). This increase in Isc was reproduced by chronic
peripheral administration of the selective CRF
1
agonist stressin-1 and the selective CRF
2 ligand,
Ucn 3, suggesting a role of both CRF receptor subtypes in this alteration. However,
intriguingly, pretreatment with antisauvagine, a selective CRF
2
antagonist, did not have any effect on chronic CRF-induced Isc increase (115).
Whether the dose of antagonist used was inefficient to block CRF effect
in
vivo remains uncertain as no dose-response studies were performed. Similar
to the effects of peripheral injections of CRF ligands, exposure of rodents
to either acute or chronic stress increases basal and stimulated Isc in the
colon (113, 127, 142-144) as well as in the ileum (93, 127, 145) and this alteration
in Isc is abolished by pretreating rats with the peripheral non-selective CRF
antagonists astressin or a-helical CRF
9-41 (112,
113, 142). Together, these data suggest the participation of both CRF
1
and CRF
2 receptors in the alterations of epithelial
secretory response induced by stress and activation of peripheral CRF signaling.
Strong evidence for a direct peripheral action of CRF peptides on epithelial
secretory response comes from
in vitro studies, performed in Ussing chambers.
While the only study performed in humans did not show any effect of the direct
administration of CRF on colonic biopsies from healthy controls on Isc (38),
in rat colonic tissue, CRF has been found to consistently increase the baseline
Isc (112, 113).
in vitro, treatment with
-helical
CRF
9-41 or astressin prevented the CRF-induced
increase in Isc (112, 114), further supporting a role for peripheral CRF receptors
located at the submucosal/mucosal level. Of note, maximal epithelial Isc responses
in rat colonic tissue have been obtained with sauvagine, a CRF agonist with
high affinity to both CRF receptors administered
in vitro at doses 200-1000
fold lower than CRF, suggesting a predominant CRF
2
effect in the modulation of secretory epithelial functions in the rat colon
(114).
It is well established that enteric neuronal reflex pathways within the enteric nervous system which control chloride secretion involve acetylcholine and serotonin (146). In support of such pathways in the effect of peripheral CRF on secretory function, hexamethonium and atropine (nicotinic and muscarinic blockers, respectively) but not bretylium (adrenergic blocker) prevented CRF-induced Isc increase in rat colonic tissue (112). Mast cells also play a key role in the CRF-induced secretory epithelial alterations as colonic tissue pretreated with doxantrazole or issued from mast cells deficient rats do not exhibit Isc changes following CRF exposure in Ussing chambers (112, 115). A number of studies also show that the watery diarrhea induced by stress or exogenous central administration of CRF in rats depends on serotonin release and the contribution of 5-HT3 receptors (88, 90), but whether this pathway is also recruited in response to peripheral CRF signaling activation is still undetermined.
Taken together, these data established the involvement of peripheral CRF signaling in the modulation of secretory function under stress
via activation of both CRF
1 and CRF
2 receptors, activation of cholinergic enteric neurons, mast cells and possibly serotonergic pathways.
Permeability
Trafficking of molecules through the intestinal epithelial barrier occurs
via
two routes: paracellular (between cells) which controls ion selectivity, nutrients
and solute permeability and/or transcellular (through cells) which allows transport
of large molecules (antigens, immunoglobulins) through epithelial cells (147).
The integrity of the epithelial barrier is regulated by a complex protein system
that constitutes tight junctions (for review see (148)). Gross changes in epithelial
permeability are measured
in vivo by the mannitol/lactulose ratio or
lumen-to-blood ratio of macromolecules such as albumin. Gut paracellular permeability
is measured
in vivo using radioactive or fluorescent probes of more than
10 Å in size (
51Cr-EDTA, FITC-dextran, FI-sulfonic
acid) (149, 150) and ex vivo using Ussing chambers to assess the flux of FITC-dextran,
the transepithelial resistance (TER) or the conductance (G=1/TER), which reflects
paracellular ion exchange and tissue
viability. Gut transcellular permeability
is assessed
ex vivo via measurements of horseradish peroxidase
(HRP, 44 kDa, 50-60 Å) flux or endocytosis.
So far, the effects of peripheral CRF administration on epithelial barrier function
in humans have not been assessed. In rats, however, acute or chronic peripheral
CRF administration stimulates colonic HRP flux
ex vivo or
51Cr-EDTA
flux
in vivo (10, 113, 115). This increase in colonic HRP flux ex vivo
appears to be CRF
2-mediated (115). In contrast,
in our own
in vivo experiments, we found that selective peripheral activation
of CRF
1 receptors in rats increased the colonic
permeability as monitored by Evans blue permeation from lumen to blood (7).
Thus far, there is no report on the influence of the peripheral CRF signaling
on ileal epithelial permeability. However, our recent experiments indicate that
the activation of either peripheral CRF receptors induces the loss of the epithelial
barrier in the ileum by reducing the expression of integral tight junctions
proteins and altering the expression of IFN-
and IL-10 (Kiank
et al., unpublished data). These effects seem to be
related to the recruitment of CRF
2 pathways
by CRF
1 activation and appear to be dose-dependent,
as shown by the protective effect of peripheral CRF
1
signaling activation at low doses (Kiank
et al., unpublished data).
In humans and rodents, stress also induces alterations of epithelial permeability.
Acute cold stress exposure enhances jejunal permeability to antigenic macromolecules
(blood-to-lumen albumin permeability) and enhances the blood-to-lumen mannitol
and xylose permeability in healthy controls (102, 141). Alterations of permeability
have also been shown
in vitro in colonic biopsies of both post-infectious
and non post-infectious diarrhea-predominant IBS patients (151, 152) and
in
vivo in the small intestine (153). Nevertheless, a direct causal relationship
between increased permeability and stress has not been established in these
studies. In rodents, both acute (restraint, WAS, cold) and chronic stress (WAS
5-10 days, maternal separation) increase the paracellular and transcellular
permeability in the colon (10, 112, 113, 127, 133, 142-144, 154, 155) and in
the ileum (93, 127, 145). At the colonic level, this alteration is abolished
by pretreatment of rats with the peripheral administration of the non selective
CRF antagonists astressin or
-helical
CRF
9-41 (10, 112, 113, 142) or the selective
CRF
1 antagonist, SSR-125543 (10), supporting
the participation of CRF
1 receptors in the modulation
of colonic permeability.
Additional support to a peripherally restricted action of CRF signaling on epithelial
permeability changes has also been obtained
in vitro. In human colonic
biopsies mounted in Ussing chambers, CRF administered on the serosal side induced
an increased uptake of HRP by endocytosis, sign of an increased transcellular
permeability, but did not affect paracellular permeability as assessed by permeation
of
51Cr-EDTA and TER (38). This result contrasts
with the increase in both paracellular and transcellular permeability observed
in rat colonic tissue after exposure to CRF, sauvagine or Ucn 3
in vitro
(112-114). This could be related to species differences in the effector mechanisms
recruited in the periphery, but those are still not well known in humans. In
rats however, it is shown that enteric nerves and mast cells are involved in
the alterations of colonic permeability induced by peripheral CRF administration
(38, 112, 115). Interestingly, alterations in paracellular permeability are
mediated by adrenergic and nicotinic nerves, whereas cholinergic, adrenergic
and nicotinic nerves all participate to the alterations of transcellular permeability
(112). The CRF receptors and effector mechanisms involved in the alterations
of epithelial permeability in the ileum remain unknown.
Thus, stress-induced activation of peripheral CRF receptors has an important impact on permeability at both the ileal and colonic levels. Together, these data suggest the participation of both CRF
1 and CRF
2 receptors in the alterations of epithelial permeability barrier in response to activation of peripheral CRF signaling or stress, with recruitment of mast cells, nicotinic, cholinergic and adrenergic enteric nerves.
EPITHELIAL DYSFUNCTION-INDUCED
IMMUNE ACTIVATION
Altered integrity of the intestinal epithelial cellular layer and tight junctions deregulation may have systemic consequences and seem to be a key factor leading to the dysfunction of several organs such as lung, liver, gut, or kidney associated during septic complication that are caused by decontrolled inflammatory processes (156). Intriguingly, exposure of Fisher rats to stress before induction of a stroke by middle cerebral artery occlusion is associated with a worse stroke outcome which is linked with colonic inflammation and bacterial translocation into different organs such as mesenteric lymph nodes, spleen, liver, and lung (157). Together these data emphasize the potential clinical relevance of bacterial translocation in severely sick patients.
It is widely accepted that stress can trigger local inflammatory processes in
the gut and influences the clinical course of gastrointestinal disorders such
as peptic ulcer, IBS or IBD. The increased passage of antigens, commensal microorganisms
or even pathogens in the lamina propria subsequent to an epithelial barrier
breach, contributes to the development of inflammatory processes (80, 112, 114,
133, 145, 158, 159). An enhanced bacterial translocation was demonstrated during
chronic psychological stress and during colitis, which seems to exaggerate the
course of colonic inflammation (160-162).
E. coli bacteria are also present
in the mucosa during ileal inflammation and Toll-like receptor 4 (TLR4) signaling
exacerbates ileitis
via enhancing the local release of IFN
and nitric oxide from immune cells, thus further damaging the local tissue (163).
Finally, it was shown that intestinal inflammation results in a prolonged impairment
of colonic epithelial secretion, which increases bacterial translocation (164)
and may further boost inflammatory processes triggering chronic diseases such
as IBD. The underlying role of stress-related colonic activation of CRF signaling
and related effects on local immune cells under these conditions is still to
be investigated.
VISCERAL PAIN
A role for peripheral CRF signaling in the development and expression of visceral pain is well documented by several reports in both humans and rodents (7, 18, 165-169). A systemic injection of the preferential CRF
1 agonist, ovine CRF (170) lowers pain thresholds to repetitive rectal distensions in healthy humans (165, 166). In rats, peripheral injection of CRF induces visceral hypersensitivity to CRD (169), an effect reproduced by the intraperitoneal administration of the selective CRF
1 agonist, cortagine in rats and mice (7). Likewise acute stress (cold, noise) and chronic stressful events have also been shown to increase the visceral sensitivity to rectosigmoid distension in humans, in particular IBS patients (171, 172). In rodents as well, several studies support a strong association between stress (acute or chronic) and increased visceral sensitivity to CRD (123, 124, 150, 173-176).
Converging evidence support the involvement of peripheral CRF
1
receptors in these effects. First, intravenous administration of the non-selective
and peripherally-restricted CRF receptors antagonists,
-helical
CRF
9-41 or astressin reduced visceral hyperalgesia
in diarrhea-predominant IBS patients subjected to colonic electrical stimulation
(167, 168). In earlier experiments with rats repeatedly exposed to WAS for 10
days, we found that peripheral administration of astressin before each stress
session could prevent the development of visceral hyperalgesia supporting the
participation of a peripheral component to the development of visceral hypersensitivity
(177). Lastly, the visceral hyperalgesia induced by peripheral injection of
cortagine in rats is abolished by peripheral, but not central, administration
of the non selective CRF receptor antagonist astressin at equivalent dose (7).
To date, there are no reports about peripheral CRF signaling activation effects
on visceral sensitivity in the ileum. Pain associated fibers (myenteric AH neurons)
which are known to respond to CRF
via CRF
1
receptors activation (42) have however been described in the ileum (42, 178)
and open the possibility that peripheral CRF signaling may also contribute to
the pain and discomfort in the ileal segment.
Peripheral CRF induces mast cells degranulation (10) which can in turn lead to the development of visceral hypersensitivity
via the release of several preformed or newly generated mediators (
e.g. histamine (151, 179), tryptase (179), prostaglandin E2 (180), nerve growth factor (NGF) (123)) that can activate or sensitize sensory afferents (181, 182). Additionally, the disruption of the intestinal epithelial barrier by peripheral CRF signaling activation as detailed earlier may increase the penetration of soluble factors (antigens) into the lamina propria, which can lead to nociceptors sensitization as shown for stress (151, 152) and may be independent from mast cell activation, as suggested for persistent stress (182, 183). Increased intestinal permeability is indeed a phenomenon that appears as a prerequisite for the development of visceral hypersensitivity in both humans and rodents (150, 152, 184).
Taken together, these reports suggest that enhanced peripheral activation of CRF/CRF
1 signaling in addition to central activation bears relevance as part of the peripheral efferent components responsible for altering the colonic visceral responses to stress
via mast cells recruitment and release of inflammatory mediators which alter the epithelial barrier function.
PATHOPHYSIOLOGICAL RELEVANCE
OF PERIPHERAL CRF SIGNALING IN IBS AND IBD
As outlined, strong preclinical evidence suggests that activation of the peripheral CRF signaling, by mimicking stress effects, exerts a key role in the alterations of colonic and ileal propulsive motor function, visceral hypersensitivity and the epithelium including secretion, barrier and immune functions
via activation of CRF
1 receptors in the colon or CRF
2 receptors, or both, in the ileum. Multiple potential pathways recruited by stress in the periphery have been reported. Although early results in humans suggest that the peripheral CRF signaling might participate to the immune components in IBD (13, 14, 185) and it is also very likely involved in the pathogenesis of IBS (11, 186-191), additional clinical data are required to validate this concept.
To date only two double-blind, placebo-controlled clinical trials using CRF
1 antagonists in IBS patients have been performed and the results are inconclusive (192, 193). Additional studies are required to determine whether the first phase IIa clinical trial negative results reflect differential efficacy of CRF
1 antagonists, or a lack of translational application of stress-related mechanisms to the pathophysiology of IBS. Of importance, in human tissues, there is evidence of alternative splicing of CRF
1 receptors leading to eleven isoforms and dimerization of the receptors along with differential regulation under pathophysiologic conditions. This creates additional regulatory elements in the CRF
1 signaling pathways which have been shown to have biological relevance (194). The expression and regulation of alternative splicing of CRF
1 receptors in the colon, their biological actions and interaction with CRF
1 antagonists are unknown and may be additional components to take into account in light of these clinical trials. A better understanding of the molecular aspect of the peripheral CRF signaling system could pave the road to the development of novel therapeutic options to relieve stress- and inflammatory-sensitive bowel disorders.
Abbreviations:
5-HT- serotonin; AMPs- antimicrobial peptides; CD- Crohn’s disease; CRD- colorectal
distension; CRF- corticotropin releasing factor; CRF1-
corticotropin releasing factor receptor 1; CRF2-
corticotropin releasing factor receptor 2; CRF-BP- CRF binding protein; ENS-
enteric nervous system; G- conductance; GI- gastrointestinal; HRP- horseradish
peroxidase; IBD- inflammatory bowel disease; IBS- irritable bowel syndrome;
IFN-
interferon ;
IL- interleukin, IR- immunoreactivity; Isc- short circuit current; LP- lamina
propria; LPMCs- lamina propria mononuclear cells; LPS-lipopolysaccharide; MAPK-mitogen
achvated protein kinase; PK-protein kinase; ERK1/2-extracellular signal-regulated
kinase 1/2; MNP- myenteric neuronal plexus; NK- natural killer; PAR-2- protease
activated receptor 2; SNP- submucosal neuronal plexus; TER- transepithelial
resistance; TLR4- Toll-like receptor 4; UC- ulcerative colitis; Ucn- urocortin;
WAS-water avoidance stress.
Acknowledgements: This review is part of studies supported by the VA
Research Career Scientist Award (YT), German Research Foundation Grant KI 1389/2-1
(CK), NIH grants R01 DK-57238 (YT) and P50 DK-64539 (YT, ML). The authors thank
Miss E. Hu for reviewing the manuscript.
Conflict of interest: None declared by the authors.
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