chronic inflammatory state. In addition, IBS is a highly prevalent functional bowel disorder,
which accounts for up to 40% of gastroenterology outpatients, hence making it an important趁虚而入的意思
clinical entity (Taché and Brunnhuber 2008).
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The association or impact of psychosocial factors on IBD and IBS prompted investigations to
unravel the contributions of stress-related mechanisms in their pathophysiology in order to
develop novel therapeutic options targeting the pathways. One principal effector of stress
responsive systems is the 41 amino acid corticotropin releasing factor (CRF) that is relead
in the brain in respon to stressors and plays a pivotal role to activate the hypothalamic-
pituitary-adrenal (HPA) axis (Lightman, 2008). Brain CRF also acts as a neurotransmitter to
modulate behavior and activity of the autonomic nervous system (Taché et al. 2009). In
addition, the gut contains peripheral CRF signaling pathways (Fekede and Zorrila, 2007;
Stengel and Taché 2009, Taché and Bonaz 2007) that, along with the brain CRF, can contribute
to stress-related progression and exacerbation of IBD and IBS manifestations by modulating
the autonomic and enteric nervous systems as well as immune function (Fukudo 2007; Gross
and Pothoulakis 2007; Mawdsley and Rampton 2005; Paschos et al. 2009; Taché and
Brunnhuber 2008).
In this review, we will outline experimental and clinical evidence to show that the central and
peripheral CRF systems modulate intestinal inflammation, and show that CRF receptors may
be components of the inflammatory process in IBD and post-infectious IBS, which is relevant
to mechanisms underlying the susceptibility of the dias to stress.CRF signaling: a brief overview Corticotropin-releasing factor, a 41-amino-acid peptide, is a major mediator of the endocrine arm of the stress respon by centrally stimulating the HPA axis. Neurons of the parvocellular part of the paraventricular nucleus (pPVN) of the hypothalamus produce CRF. The neuropeptide is relead into the portal blood vesls of the Zona externa of the median
eminence and reaches the pituitary gland where it binds to CRF 1 receptors localized on
corticotroph cells in the anterior pituitary, thereby inducing the cretion of adrenocorticotropin
hormone (ACTH) which stimulates glucocorticoid cretion from the adrenal gland (Lightman,
2008). Other CRF-related peptides include urocortin 1 (Ucn 1), Ucn 2 and Ucn 3 which bear
high structural similarities to CRF and high conrvation throughout evolution (for review e
Fekete and Zorilla 2007; Stengel and Taché 2008). CRF and urocortins are also expresd in
peripheral tissues and can be relead by regional nsory and sympathetic nerves, immune
cells, and gut enteroendocrine and enteric cells to act locally (Fekede and Zorrila, 2007; Karalis
et al. 1991; Liu et al. 2006).
Both CRF and urocortins interact with CRF 1 and/or CRF 2 receptors which are members of the
B1 subfamily of ven-transmembrane-domain receptors and show 70% quence homology
(Hillhou and Grammatopoulos, 2006; Markovic et al. 2008). Eleven alternative splice
variants of CRF 1 receptors have been identified in humans, in addition to three others in rats,
four in mice, and nine in hamsters (Hillhou and Grammatopoulos 2006; Stengel and Taché
2008). Expression of the variants is tissue specific and can be modified by environmental
factors (Fekete and Zorilla 2007; Hillhou and Grammatopoulos 2006). Recent studies point
to functional relevance of the different isoforms by modifying CRF actions in target tissue,
either attenuating or amplifying the signaling of functional CRF 1a receptors (Markovic et al.
2008). In humans, CRF 2 receptor signaling splice variants include the subtypes 2a, 2b, and 2c,
whereas most other mammals only express 2a and 2b isoforms with a distinct expression pattern
in different tissues (Hauger et al. 2003; Stengel and Taché 2008). Importantly, the binding
affinities of CRF and urocortins to CRF 1 and CRF 2 receptors differ considerably (Hauger et
爬山虎的叶子al. 2003). CRF displays its highest affinity to CRF 1 receptors (Hauger et al. 2003). Ucn 1 shows
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an equal affinity to both CRF receptor types whereas Ucn 2 and Ucn 3 are lective agonists
for CRF 2 receptor (Hauger et al. 2003).
CRF receptors are G-protein coupled receptors and most physiological actions of CRF in the brain and periphery involves the coupling of CRF and urocortins to G αs proteins that stimulate cAMP mediated signaling cascades (Hauger et al., 2003). Upon agonist activation, both CRF 1 and CRF 2 receptors can also be coupled to multiple G α-subunits with an order of potency:G αs >G αo >G αq/11>G αil/2>G αz (Hillhou and Grammatopoulos 2006). Differences in the coupling characteristics of CRF receptors/G protein have been obrved within tissues as well as with inbred animal strains (Hauger et al. 2003; Hillhou and Grammatopoulos 2006;Pioszak et al. 2008). G-protein signaling after ligand receptor interactions can increa intracellular Ca 2+ concentrations or result in the activation of different phosphokinas A, B,and C. It can also modify the phosphorylatio
n pattern of intracellular proteins and thereby activate mitogen-activated protein kinas (MAPKs) such as ERK1/2 and p38/MAPK (Hillhou and Grammatopoulos 2006; Grossini et al. 2009; Gutknecht et al. 2009;). By the multiple signaling pathways, CRF receptor activation influences neuronal, endothelial,endocrine, smooth muscle, epithelial and immune cell activity which are increasingly understood but need further characterization at specific target cells (Black 2002; Hillhou and Grammatopoulos 2006).The immune system of the gastro-intestinal tract: a brief overview Due to its position and function, the gastrointestinal tract, along with the other viscera containing mucosal compartments such as the respiratory and reproductive tracts, reprents the first line of defen of the body against luminal antigens and pathogens derived from the environment. Intestinal epithelial cells (IECs) form a single layer of polarized cells, tightly aled by tight junctions that impede paracellular transport of small macromolecules via the paracellular route. IECs produce high amounts of mucus and crete antimicrobial peptides that limit bacterial colonization (Al-Sadi et al. 2009; Kraehenbuhl and Corbett 2004;
Macpherson et al. 2008). Under physiological conditions, the epithelial barrier remains
permeable to a few bacteria and antigens in follicle-associated epithelia such as M cells which
overlay aggregated mucosal lymphoid tissue, allowing the gut to induce tolerogenic reactions
(Al-Sadi et al. 2009; Kraehenbuhl and Corbett 2004). If bacteria and antigens pass at sites of
leaky tight junctions, however, there is induction of a transient local low-grade
proinflammatory cytokine respon that is esntial to inhibit invasion of microorganisms into
the body (Al-Sadi et al. 2009; Kraehenbuhl and Corbett 2004; Macpherson et al. 2008). This
respon is rapidly counter-regulated and does not result in a measurable systemic
proinflammatory state.
Mechanisms that prevent inflammation in the intestine include the production of neutralizing
immunoglobulins (Ig) such as IgA (Kraehenbuhl and Corbett 2004; Macpherson et al. 2008)
and a low expression of pattern recognition receptors (PRRs) and co-stimulatory molecules on
antigen-prenting cells, which are esntial for T cell activation (Akira et al. 2006;
Kraehenbuhl and Corbett 2004; van Vliet et al. 2007). There is also local relea of the cytokine,
thymic stromal lymphopoietin (TSLP), which inhibits the differentiation of dendritic cells
(DCs) that drive a proinflammatory T helper (Th) cell 1-mediated immune respon (Liu et al.
2007). The anti-inflammatory cytokine bias in the gut is basically maintained by high cretion
of interleukin (IL)-10 and tissue growth factor-β (TGF-β) which are relead by regulatory T
cells (Makita et al. 2007). IL-10 suppress both Th-1 and Th-2-cell respons as well as the
innate immune functions (Kraehenbuhl and Corbett 2004). Thus, under physiological
conditions, there is a phenomenon of tolerance where the gut is in a state of active
immunosuppression, which prevents a destructive immune respon while still eliminating
microbes and antigens by neutralization or induction of a local, controlled low-grade and食堂安全管理制度
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transient inflammation (Gonzalez-Rey et al. 2007; Kraehenbuhl and Corbett 2004). However,
when pathogens or incread numbers or bacteria pass the intestinal barrier, a measurable local
proinflammatory respon is induced to eliminate the threatening agents.
Stress modulate the activity of neuroendocrine, immune and gastrointestinal systems (Black
2002; Lightman 2008; Taché and Brunnhuber 2008; Webster Marketon and Glar 2008,).
Altered relea of neuroendocrine factors, such as glucocorticoids, vasoactive intestinal
peptides, neurotensin, adrenomedullin, catecholamines or CRF and its related peptides, by
stress, may disturb the intestinal cytokine balance and intestinal barrier integrity (Gonzalez-
Rey et al. 2007; Gross and Pothoulakis, 2007; Santos et al. 2008). Inflammation is a main
component in the pathogenesis of IBD (Shih and Targan 2008; Gross and Pothloulakis,
2007) and there is increasing evidence that low grade proinflammatory process may also
have a role in the development of IBS particularly post-infectious IBS (De Giorgio and Barbara
2008; Spiller and Gard, 2009; Santos et al. 2008).CRF receptor signaling and IBD IBD is associated with a measurable inflammatory respon in the gut which includes activation of the innate immune respon via recognition of microbial structures by pattern recognition receptors (e.g. Toll-like receptors) as well as activation of the adaptive immune system driving Th-1 and Th-17 respons that trigger the inflammatory process in the intestine (Arneau et al. 2007; Shih and Targan, 2008). Th1 respons induce a proinflammatory cytokine bias,including incread relea of interferon-gamma (IFN γ) or tumor necrosis factor-alpha (TNF α) to defend microbial and viral infections, but also perpetuate autoimmune respons.Excessive proinflammation may lead to uncontrolled tissue damage. In addition, Th17 cells produce IL-17, which promotes a local inflammatory respon including IL-6 and IL-8 relea and neutrophils chemotaxis to remove microbes. By triggering an excessive inflammatory respon, Th17 cells contribute to the development and exaggeration of autoimmune dias such as IBD (Shih and Targan, 2008). Under physiological conditions, regulatory T (Treg)-
猪气喘病and Th2 cell driven respons, which include the relea of IL-10, TGF-β and IL-4, counteract
the Th1 mediated microbicidal and autoimmune actions (Arneau et al. 2007, Sanchez-Munoz
et al. 2008).
Considerable evidence show that psychological stress increas the risk of relap and/or
exacerbation of IBD symptoms (Mawdsley and Rampton 2005). Activation of the CRF system
神采飞扬的意思may be part of the underlying mechanism of stress-related modulation of IBD activity as
reviewed recently (Gross and Pothoulakis 2007; Mawdslely and Rampton 2005; Paschos et
al., 2009). Stressors such as hypothermia, hyperosmolarity, and hypoxia as well as
inflammatory stimuli induce CRF cretion in human lymphocytes and mou splenocytes
(Baigent and Lowry; 2000; Bellinger et al. 2001; Kravchenco and Furalev 1994). In veral
tissues, CRF signaling promotes the immune respon: CRF stimulates human lymphocyte
proliferation by increasing IL-2 receptor expression and enhancing the production of IL-1 and
IL-2 (Singh and Leu 990). In addition, CRF and/or urocortins evoke enhances endotoxin-
induced cytokine relea (TNF α, Il 1 and IL-6) from mice peritoneal macrophages, chemotaxis
of mononuclear cells and induces macrophage activation which is associated with local relea
of oxidative mediators and proinflammatory cytokines (Agelaki et al. 2002; Black 2002;
Koshida and Kotake 1994; Moss et al. 2007; Tsatsani et al. 2006, Tsatsani et al. 2007; Wlk et
al. 2002). In addition, urocortins are expresd in veral immune cells (Gravanis and Margioris
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2005; Muramatsu et al. 2000) and can evoke a proinflammatory respon. Urocortin 1 induces
IL-6 relea in a time- and do-dependent manner which is associated with the activation of
ERK and p38 MAP kinas and stimulation of nuclear factor kappa B (NF κB) in
cardiomyocytes (Huang et al. 2009).
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In the intestine, activation of CRF signaling results in promoting the proinflammatory respon.CRF expression is upregulated at the gene and protein levels in inflammatory, menchymal and neuronal cells in rat cecum in respon to peptidoglycan-induced colitis. Converly, in experimental models of intestinal inflammation, CRF-deficient mice display an attenuated inflammatory respon (Gay et al. 2008; Kokkotou et al. 2006). Clinical studies showed that the colonic mucosa of patients with IBD displays incread numbers of CRF-immunoreactive enterochromaffin and macrophage cells (Gross and Pothoulakis, 2007). Other reports indicate an incread expression of CRF immunoreactive cells in the lamina propria, namely in mononuclear and macrophage in colonic biopsies from patients suffering from active UC (Gross and Pothoulakis, 2007). Likewi, Ucn 1 expression is upregulated in lamina propria macrophages and expresd in enterochromaffin cells and IECs in patients with UC with a positive correlation with the intensity of the dia (Gross and Pothoulakis, 2007; Muramatsu et al. 2000; Saruta et al. 2004).The contribution of the CRF1 receptor signaling in colonic inflammation induced by trinitrobenzene sulfonic acid combined six weeks later with repeated nociceptive stress of colorectal distensions has been demonstrated by the reduction in
the number of colonic neutrophils and eosinophils in rats pretreated with CRF 1 antagonist before exposure to repeated colorectal distentions (Saito-Nakaya et al. 2008).Further studies also established the involvement of the Ucn 2-CRF 2 receptor signaling pathway in the modulation of colonic inflammation (Gross and Pothoulakis, 2007; Paschos et al.2009). Patients who suffer from IBD display high expression of Ucn 2 and CRF 2 receptors in the colon (Moss et al. 2007). Likewi, in a rat model of chemically-induced colitis, Ucn 2expression is incread in a large population of infiltrating immune cells of the distal colon,and associated with compensatory down-regulation of CRF 2 receptors in neurons of the myenteric plexus (Chang et al. 2007). Moreover, CRF 2 receptor deficient mice show a reduced susceptibility to intestinal inflammatory respon to experimental induction of colitis
(Kokkotou et al. 2006; Moss et al. 2007). At the cellular level, CRF can modulate macrophage function by augmenting LPS-induced proinflammatory cytokine production in the cells which is CRF 2 receptor dependent and enhance Toll-like receptor (TLR)-4 gene expression (Tsatsani et al. 2006). It was also demonstrated that CRF, Ucn 1 and Ucn 2, acting through both CRF 1 and CRF 2 dependent signaling pathways, enhances TNF-α transcription in macrophages (Tsatsani et al. 2007). Moss et al. demonstrated in human non-transformed NCM460 colonocytes that Ucn 2 induces NF κ
B signaling via CRF 2 receptors which results in an exaggerated relea of the chemokine IL-8 (Moss et al. 2007).
Besides the described effects of CRF and its related peptides acting on CRF receptors located on different immune cells, mast cells are also targets of stress and CRF receptor signaling action in inflammation (Farhadi et al. 2007). The plasticity of mast cells allows for a rapid and
lective immune respon. Mast cells can relea a variety of preformed or newly synthesized mediators, among tho proteas and inflammatory mediators including histamine, chyma,trypta, IL-1β and TNF-α (Rao and Brown 2008 Siddiqui and Miner 2004). In particular, mast cell trypta or chyma (RMCPII) (He 2004) activate protea activated receptor-2 (PAR-2)on intestinal epithelial cells and heighten paracellular permeability (Demaude et al. 2009; He 2004; Santos et al. 2008). Therefore, mast cells are important effectors of the intestinal epithelial respon to stress and inflammation, which include ion cretion abnormalities,macromolecules incread permeability and mucin relea (Farhadi et al. 2007; Santos et al.2008). In the human colonic mucosa, CRF receptors are expresd at the gene and protein levels exclusively in resident mast cells, thought not in all (Wallon et al. 2008). In the rat colon,the prence of CRF receptors on mast cells and their modulation by CRF are supported by functional reports (Santos et al. 2008), while im
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