Corticotropin-Releasing Factor (CRF) Family of Neuropeptides – Role in Inflammation

Corticotropin-Releasing Factor (CRF) Family of Neuropeptides – Role in Inflammation 635

Corticotropin-Releasing Factor (CRF) Family of Neuropeptides – Role in Inflammation A Gravanis and A N Margioris University of Crete, Heraklion, Greece ã 2007 Elsevier Inc. All rights reserved.

The Corticotropin Releasing Factor Family of Neuropeptides and Their Receptors The Inflammatory Response Corticotropin Releasing Factor Peptides and Immune Cells Corticotropin Releasing Factor Peptides Modulate Inflammation at a Local Paracrine Level Corticotropin Releasing Factor Antagonists as New Therapeutic Agents of Inflammatory Diseases

Glossary Corticotropin releasing factor (CRF)

Inflammation

Urocortins

A hypothalamic neuropeptide produced in response to stress; it regulates the production of cortisol from the adrenal glands via the hypothalamic-pituitaryadrenal axis. CRF is also produced in the brain and peripheral tissues, including the immune cells. The first line of immune defense against a broad spectrum of molecules; the clinical sign characteristics are swelling, redness, fever, and pain. It can be acute or chronic, local or generalized. Exposure to chemicals, microorganisms or physical damage initiates the inflammatory response characterized by a cellular and noncellular (exudative) component. Neuropeptides with high homology/ chemical resemblance to CRF. They are produced in the brain and peripheral tissues, including the immune cells. There are three urocortin molecules: urocortin 1, urocortin 2 (or stresscopin-related peptide), and urocortin 3 (or stresscopin).

The Corticotropin Releasing Factor Family of Neuropeptides and Their Receptors Corticotropin Releasing Factor

CRF, a 41-amino-acid hypothalamic peptide, is the primary hypothalamic hormone involved in the mammalian response to stress. Stress is defined as any threat to homeostasis. CRF coordinates the homeostatic

mechanisms necessary for an organism to cope with internal or external threats. The stress-regulating CRF is produced in the parvocellular neurons of the paraventricular hypothalamic nucleus, which receive innervation from higher central nervous system (CNS) areas and from the periphery. CRF is released into the hypophysial portal circulation and travels to anterior pituitary lobe, where it binds to specific CRF sites, the CRF receptors type 1, stimulating the production of proopiomelanocortin (POMC) by corticotroph cells. POMC is then cleaved into adrenocorticotropic hormone (ACTH), a systemic hormone that stimulates cortisol production from the adrenal gland; cortisol is the principal stress hormone in humans. At the same time, several parvocellular CRF neurons project into locus coeruleus, the command center of sympathetic system, the second major adaptation mechanism to stress. CRF enhances central sympathetic outflow. In addition to its synthesis in the hypothalamus, CRF is also produced throughout the brain, where it works as a peptide neurotransmitter. In general, in the brain CRF stimulates the stress axes and mediates anxiogenic effects. CRF is also present in peripheral tissues including the heart, gastrointestinal (GI) tract, skin, gonads, adrenals, and several components of the immune system including the lymphocytes, splenocytes, neutrophils, mast cells, and monocytes/ macrophages. The Urocortins

There are three urocortin molecules. Urocortin 1 is a 40-amino-acid peptide first isolated from rat brain by molecular cloning in 1995. It exhibits 45% homology with CRF and 63% homology with urotensin, a neuropeptide found in teleost fish. Urocortin 1 strongly binds and stimulates the CRF1 and CRF2 receptors. Like CRF, it can stimulate ACTH secretion from anterior pituitary corticotrophs in vitro and in vivo. Urocortin 1 is more potent than CRF in decreasing feeding in both meal-deprived and freefeeding rats. Urocortin 1 suppresses feeding via CRF2 receptors. Urocortin 2, also known as stresscopin-related peptide, and urocortin 3 (stresscopin) are 38-amino-acid peptides and share high homology. They are selective ligands for the CRF2 receptor and thus they share several common effects with urocortin 1 in

636 Corticotropin-Releasing Factor (CRF) Family of Neuropeptides – Role in Inflammation

appetite suppression, delay of gastric emptying, and cardiovascular effects. They are expressed in several areas of the brain, including the hypothalamus, amygdala, and brain stem, and in the periphery in the GI tract, skin, adrenals, and cardiovascular system. The Corticotropin Releasing Factor Receptors

The biological effects of CRF peptides are mediated by CRF receptor type 1 (CRF1) and CRF2. CRF2 exists in at least three isoforms, resulting from alternative splicing, the CRFa, CRFb, and CRFg. The CRF receptors belong to the class B subdivision of G-protein-coupled membrane receptor superfamily. CRF1 and the CRF2a and CRF2g receptors are expressed throughout the brain, whereas CRFR2b is mainly expressed in the periphery, in the lung, skeletal muscles, gonads, cardiac myocytes, skin, GI tract, adrenals, and many immune cells. In the CNS, the CRF2 receptors mediate a central anxiolytic response, opposing the general anxiogenic effect of CRF, which is mediated by the CRF1 receptor. Mice overexpressing CRF show anxiogenic-like responses compared to wild-type mice, whereas mice lacking the CRF1 receptor show an anxiolytic-like behavior. It thus appears that the activation of the CRF1 receptors prepare the organism to respond to stress at a somatic level (activation of the hypothalamuspituitary-adrenal axis and the sympathetic nervous system) and behaviorally (i.e., the anxiogenic-like response). CRF2 receptors adapt the organism to stress and ameliorate the stress response. Finally, a third type of receptor, the CRF-binding protein (CRFBP), is a pseudoreceptor whose primary function is to compete with CRF receptors for the CRF ligands, thus making it unavailable to the bioactive CRF receptors. CRFBP is mainly expressed in the CNS and peripheral nervous system.

The Inflammatory Response A Brief Description of Inflammation

Inflammation is the first line of immune defense against a broad spectrum of molecules. This biologically ancient and nonspecific process is part of the innate immunity system. It does not possess a mechanism for memorizing the offending event and, thus, does not confer a lasting immunity against it. If innate immunity is overwhelmed, then a biologically more recent immune mechanism takes control – acquired immunity, a complex process that memorizes the event and confers lasting and specific immunity.

Basic Concepts in the Physiology of the Inflammatory Response

Inflammation can be acute or chronic, local or generalized. Exposure to chemicals, microorganisms or physical damage initiates the inflammatory response characterized by a cellular and a noncellular (exudative) component. The first cells to gather at an inflammation site are the neutrophils (polymorphonuclear cells). Neutrophils live for 1–2 days, and they are gradually replaced by monocytes, which mature to macrophages. All these cells cross the vascular wall and enter the inflammation site. There, they secrete pro- and anti-inflammatory substances, including cytokines, chemokines, and adhesion molecules; clean the area from microbes and cellular debris by phagocytosis; chemoattract other immune cells; and finally act as antigen-presenting cells. The pro-inflammatory cytokines interleukin (IL-)1 and IL-6 and tumor necrosis factor (TNF-)a activate endothelial cells to produce specific membrane receptors (vascular adhesion molecule 1, VCAM-1; intercellular adhesion molecule 1, ICAM-1; selectins), which bind immune cells. The exudative component consists of fluid moving from the intravascular space, due to the increased permeability of the vascular wall. It consists of fibrins and several types of immunoglobulins. These phenomena at an inflammation site produce the clinical characteristics of inflammation: swelling, redness, fever, and pain (tumor, rubror, calor, and dolor, in Latin). If the inflammatory response is large, it can cause systemic symptoms including fever, chills, fatigue, loss of appetite, and mental confusion. If the acute inflammatory response cannot isolate and destroy the offending agent, T lymphocytes take over, shifting the response to chronic inflammation by recruiting B lymphocytes, macrophages, and fibroblasts. Note that arteriosclerosis is now considered the most significant (in terms of threat to health) consequence of a chronic low-level inflammatory response. Corticotropin Releasing Factor, Urocortins, and Inflammation

CRF regulates the production of cortisol via the hypothalamic-pituitary-adrenal axis. Cortisol, like all glucocorticoids, affects the immune system at multiple levels. Most of its effects are suppressive. Indeed, glucocorticoids are used extensively in suppressing the immune system in autoimmune diseases. During the last 20 years, it became gradually apparent that CRF and the urocortins affect the immune system independently of cortisol in a direct and paracrine

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manner via the CRF receptors present, as previously stated, in most immune cells. CRF and the urocortins reach the immune cells and the sites of inflammation either via axonal transport through the autonomic nerves or by being produced ad hoc by the epithelial, the endothelial, and the immune cells themselves. Indeed, it has been shown that human mast cells, lymphocytes, monocytes/macrophages, murine neutrophils, and splenic T lymphocytes produce the CRF family of peptides as well as their receptors. In addition, it is now know that the levels of these peptides and their receptors increase at inflammation sites at a level parallel to the degree of the inflammatory response. In particular, high levels of CRF and urocortins have been found in experimentally induced inflammation, for example, in the inflamed synovia of patients with rheumatoid arthritis, in the inflamed colonic mucosa of patients with ulcerative colitis, and in the inflamed uvea. The concentration of CRF peptides also increases in human endometrium at the sites of egg nidation and implantation, both well-described inflammatory phenomena.

Corticotropin Releasing Factor Peptides and Immune Cells Mast Cells

It appears that mast cells represent one of the principal immune cell targets of CRF peptides. Indeed, the exposure of mast cells to CRF results in their immediate degranulation of pro-inflammatory mediators, an effect blocked by CRF1 antagonists (molecules that bind to the CRF1 receptor, inhibiting its function). Human mast cells synthesize CRF, urocortins, and CRF1 and CRF2 receptors. The activation of immunoglobulin E receptor induces the synthesis and secretion of both CRF and urocortins. It has recently been suggested that in the skin, mast cells, neurons, and keratinocytes interact via several substances including the CRF peptides. This cutaneous cellular network may be involved in the exacerbation of atopic dermatitis, psoriasis, and other skin ailments following stressful situations (neurogenic inflammation). Macrophages

Macrophages are among the initiator cells during the inflammatory response and represent the main source of pro-inflammatory cytokines. The activation of macrophages occurs through antigenic signals, including bacterial lipopolysaccharide (LPS), which binds to toll-like receptor (TLR-)4; the activation

of the latter results in an induction of cytokine production and secretion. CRF augments LPS-induced pro-inflammatory cytokine production from macrophages. This effect of the CRF family of peptides appears to be due to their effect on the expression of TLR-4 receptors on macrophages. This effect occurs at the transcriptional level. Indeed, CRF peptides activate TLR-4 in macrophages transfected with a construct containing the proximal region of the TLR-4 promoter linked to luciferase gene. This effect is abolished on mutation of the proximal to the initiation codon PU.1 binding site or on mutation of the activating enhancer binding protein (AP-)1 binding element. In addition, CRF peptides block the wellknown inhibitory effect of LPS on TLR-4 expression.

Corticotropin Releasing Factor Peptides Modulate Inflammation at a Local Paracrine Level Multiple published reports suggest that CRF and the urocortins modulate the inflammatory response at a local, ad hoc level. Indeed, several published reports have shown that the CRF peptides affect the inflammatory response at several steps, including neutrophil and macrophage recruitment and migration, phagocytosis, production of cytokines and chemokines, production of adhesion molecules, capillary permeability, angiogenesis, and antigen presentation. Furthermore, the blockade of CRF receptors in several experimental models of inflammation or in stress-induced colitis suppresses immune cell migration, exudate production, the levels of cytokines, ionic and macromolecular permeability of vascular wall, and several other phenomena associated with inflammation. Corticotropin Releasing Factor Peptides in the Gastrointestinal Tract

As previously stated, CRF, the urocortins, and their receptors are expressed throughout the GI tract. CRF is mainly produced by the normal enterochromaffin cells in the lower GI tract, whereas the urocortins are produced mostly in the upper GI tract by epithelial cells. The activation of the CRF1 receptor stimulates colonic motility, whereas the activation of the CRF2 receptor inhibits gastric emptying. Gastrointestinal inflammation As previously stated, CRF and urocortins play a major role in the inflammatory phenomena taking place in the GI tract. In patients with ulcerative colitis, CRF intensifies mucosal inflammation in a paracrine manner. Thus, in the lower GI tract, CRF appears to be a major

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pro-inflammatory agent. In the stomach, the story appears to be a little different. Urocortin appears to be the major player in the stomach, where it acts as an anti-inflammatory agent. We have studied the role of stomach urocortin in humans with Helicobacter pylori (HP) gastritis. The concentration of urocortin is higher in gastric biopsies from patients with active HP gastritis than in normal controls. Following the apparent eradication of HP infection, by clinical and microscopic criteria, urocortin levels increase dramatically compared to pretreatment values. The nonresponders to HP eradication treatment do not appear to be able to elevate their levels of urocortin 1 in their gastric epithelium. In summary, it appears that CRF plays a pro-inflammatory role in inflammatory diseases of the bowel, whereas urocortins play an anti-inflammatory role in the stomach. These differences between upper and lower GI tracts may explain in part the lack of severe chronic inflammatory diseases in the stomach compared to the prevalence of chronic inflammatory bowel syndromes. Corticotropin Releasing Factor Peptides and Endometrial Decidualization

CRF, the urocortins, and their receptors are expressed in the human endometrium, the maternal reception area for the fertilized egg. During the early stages of egg apposition, endometrial stroma is differentiated into decidua, a thick and sticky area that attracts and traps the fertilized egg. The decidualization of endometrial stroma has characteristics of a local aseptic inflammatory reaction, playing a crucial role in the implantation of the fertilized egg and the continuation of pregnancy. It now appears that the CRF peptides play a major role in the decidualization of endometrial stroma. Indeed, they potentiate the decidualizing effect of progesterone, the principal gonadal steroid hormone of pregnancy. Interestingly, progesterone appears to induce the expression of endometrial CRF, thus forming a local self-augmenting loop with the CRF peptides. In addition to progesterone, several other locally produced pro-inflammatory immune factors modulate decidualization, including prostaglandins and interleukins. Endometrial CRF peptides and the interleukins interact with progesterone to fine-tune and control the phenomenon of decidualization. The sequence of events appears to be as follows. Progesterone, in addition to its strong direct decidualizing effect, induces the production of endometrial CRF peptides, which potentiate the effect of progesterone on stromal decidualization. They also affect local immune modulators inhibiting, among others, the enhancing effect of prostaglandin E2 (PGE2), inducing the inhibitory effect of IL-1 and

stimulating the inducing effect of IL-6. This complex interaction results in the optimal decidualization of human endometrium, making it ready to receive the fertilized egg. Endometrial implantation of the fertilized egg Apart from the endometrium, the implanting blastocyst (i.e., the fertilized egg composed of approximately 16–32 cells) also secretes several pro-inflammatory mediators, including IL-1 and PGE2. Blastocyst-deriving IL-1 plays an essential role in the implantation process, inducing the production of endometrial CRF peptides at the very site of implantation, rendering thus the local endometrial surface extremely adhesive for its attachment. This process leads to the formation of the egg nidus. The pivotal role of the CRF peptides on egg implantation is supported by several lines of evidence showing a significantly higher concentration of CRF peptides at the early implantation site compared to the interimplantation uterine areas. In addition, IL-1 receptor antagonists block egg implantation and early pregnancy in mice. In vivo experiments in mice have shown that intraperitoneal injections of CRF antibodies at day 2 of pregnancy decrease the number of fetuses by at least 60%. These data are further supported by experiments in rats using CRF1 receptor antagonists, which cause a dramatic reduction of the number of implantation sites. Thus, blocking of CRF has an antinidation effect at an early stage of pregnancy. Recent experimental findings support this hypothesis. It should be noted that the implanting egg should be viewed as a semixenograft containing paternal antigens, which may activate the maternal immune system, leading to embryo resorption. CRF, by stimulating the expression of the pro-apoptotic FasL protein in the decidual and trophoblastic cells, induces apoptosis (a genetically programmed form of cell death) of the surrounding maternal T lymphocytes, thus rescuing the implanted egg from the maternal immune defense. Expression of Fas ligand by fetal extravillous trophoblast cells induces apoptosis of activated T lymphocytes expressing the Fas receptor on their membranes. Inadequate CRF-mediated self-induction of FasL in extravillous trophoblasts may cause recurrent spontaneous abortions. Indeed, bridging of the local immune privilege may be detrimental to the developing fetus. These findings may also lead to new insights into the pathophysiology of preeclampsia. Corticotropin Releasing Factor Peptides in the Vascular Endothelium

Multiple reports support the hypothesis that the urocortins, acting via the CRF2 receptors, suppress

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locally produced inflammatory responses, the main cause of arteriosclerosis. Indeed, the CRF2 receptors are highly expressed throughout the human cardiovascular system. Interestingly, urocortins and the CRF2 receptor are also highly expressed by the endothelial cells of coronary arteries. Statins, the anticholesterol medications, induce the expression of vascular endothelium urocortins and their receptors. The infusion of urocortins affects human vasculature in several ways. They cause a potent vasodilation in an endothelium-independent manner. They protect cardiomyocytes during inflammation of the coronary vasculature via the suppression of angiotensin II-induced reactive-oxygen-species production from vascular endothelial cells. Urocortins also inhibit the apoptosis of mesenteric arterial smooth muscle cells via L-type calcium channels in spontaneously hypertensive rats. Corticotropin Releasing Factor Peptides in the Heart

Urocortin 1, urocortin 3, and the CRF2 receptor are expressed in human heart. Urocortins, via the CRF2 receptor, have multiple and potent cardioprotective effects. They have an anti-apoptotic effect on cardiomyocytes. More specifically, following cardioplegic arrest and subsequent reperfusion of hearts, cardiomyocytes die from apoptosis through mitochondrial injury. Urocortins protect cardiomyocytes from mitochondrial-mediated apoptosis. Urocortins also protect the ischemia-reperfusion injury of the heart muscle by inhibiting free radical activity. Finally, the infusion of urocortins ameliorat es the hemodynamic, hormonal, and renal changes t hat occur during heart failure. CRF cardiomyocyte apoptosis Apoptosis contributes to myocyte cell loss in a variety of cardiac pathologies, including cardiac failure and pathologies related to ischemia/reperfusion injury. The apoptotic process involves pro- and anti-apoptotic proteins. Indeed, apoptosis occurs when the equilibrium between pro- and anti-apoptotic mediators is disturbed. Cardiac urocortin expression is enhanced by ischemia/reperfusion injury in vitro, and the addition of exogenous urocortins reduces cell death caused by ischemia/reperfusion. In the isolated perfused heart, urocortins improve hemodynamic recovery and partially prevent the reduction in high-energy phosphates following ischemia/reperfusion. It now appears that cardiac urocortins may play a central role in cardiac myocyte protection against iatrogenic ischemia/reperfusion injury associated with bypass surgery. Indeed, it is now obvious that synthetic CRF2 receptor agonists may be extremely important

in cardioplegic therapies, ischemia/reperfusion, and heart failure. Corticotropin Releasing Factor Peptides in the Skin

A brain–skin connection with local neuroimmunoendocrine circuitry underlies the pathogenesis of allergic and inflammatory skin diseases triggered or aggravated by stress. CRF and the urocortins, along with other neuropeptides, represent part of the brain–skin connection. CRF peptides are produced in the skin, and their production is regulated by ultraviolet radiation, glucocorticoids, and the phase of hair cycle. The skin also expresses the CRF1 and CRF2. CRF1 is expressed in the epidermal and dermal compartments, whereas CRF2 is predominantly expressed in dermal structures. CRF affects several physiological parameters of epidermal melanocytes via the CRF1 receptor. Most prominently, CRF acts on epidermal melanocytes as a survival, anti-apoptotic factor under the stress of starvation as well as an inhibitor of growth factor-induced cell proliferation. Skin disorders CRF has been implicated in the pathogenesis of skin disorders exacerbated by stress. Indeed, CRF induces skin vascular permeability through neurotensin acting on mast cells. High levels of the CRF1 receptor transcript have been found in the inflammatory lesions of contact dermatitis and chronic urticaria. It should be noted that the local application of CRF on skin reduces the inflammatory and hyperalgesic processes following a vesicantinduced skin injury. CRF has been implicated in the development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin. CRF has been also found to play a role in the development of psoriasis. Corticotropin Releasing Factor Peptides in Muscle Inflammation

Fibromyalgia CRF peptides may play a role in muscle physiology and in the inflammatory phenomena taking place in this tissue. Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression, and skin sensitivity. There are no genetic or biochemical markers, and patients often present with other comorbid diseases, such as migraines, interstitial cystitis, and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased CRF and

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substance P (SP) in the cerebrospinal fluid (CSF) of FMS patients, as well as increased SP, IL-6, and IL8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis was put forward that FMS is a neuroimmunoendocrine disorder in which increased release of CRF and SP from neurons in specific muscle sites triggers local mast cells to release pro-inflammatory and neurosensitizing molecules. There is no curative treatment, although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron are helpful. Recently, new formulations containing the natural anti-inflammatory and mast cell-inhibitory flavonoid quercetin may hold promise as therapeutic agents. Muscle thermogenesis CRF may also induce skeletal muscle thermogenesis (i.e., loss of energy as heat), protecting patients against excessive intramyocellular lipid storage and hence against skeletal muscle lipotoxicity, local inflammation, and, most important, the all-important development of insulin resistance. Finally, the administration of synthetic CRF2 receptor agonists may hold promise as a treatment for the prevention of skeletal muscle atrophy.

Corticotropin Releasing Factor Antagonists as New Therapeutic Agents of Inflammatory Diseases The CRF system has been implicated in the pathophysiology of a variety of diseases, including depression, epilepsy, addiction, and Alzheimer’s. The CRF system has been also shown to play an important role in GI disorders. During the last decade, an important effort was made to develop nonpeptide micromolecular antagonists of CRF receptors with potential therapeutic applications in the treatment of several of these diseases. These, low-molecular-weight, nonpeptide CRF antagonists belong to four main classes of molecules: monocyclic, bicyclic, and tricyclic compounds and a miscellaneous category that includes compounds that are unlike the traditional smallmolecule CRF antagonists. In addition to the promising therapeutic role that nonpeptide CRF1 antagonists may have for the treatment of CNS-related diseases, these molecules may be useful in the treatment of localized chronic inflammation in several systems. For instance, these compounds open new therapeutic options in the control of lower-GI inflammatory conditions associated to CRF, such as chronic inflammatory bowel syndromes and irritable bowel syndrome. On the other hand, urocortin or synthetic micromolecular CRF2 agonists may be useful in the treatment of upper-GI

inflammatory diseases. Similarly, in reproduction, because CRF1 blockade appears to prevent implantation by reducing the inflammatory reaction of endometrium to the invading blastocyst, CRF1 antagonists may play a role as a new class of nonsteroidal inhibitors of implantation. Given the promising future of CRF antagonists in the therapy of depression and anxiety disorders, their ability to cause hypofertility and early miscarriages should seriously be borne in mind in prescribing these compounds. Synthetic CRF2 receptor agonists may be extremely important in cardioplegic therapies, ischemia/ reperfusion, and heart failure, protecting against iatrogenic ischemia/reperfusion injury associated with bypass surgery. Finally, the administration of synthetic CRF2 receptor agonists may hold promise as a treatment preventing skeletal muscle atrophy.

See also the Following Articles Anxiety; Cardiovascular System and Stress; Corticotropin Releasing Factor (CRF); Depression and Manic-Depressive Illness; Depression Models; Stress Management and Cardiovascular Disease; Ulceration, Gastric; Urocortins; Inflammation; Cardiovasular Disease, Stress and; Stress, NPY and Cardiovascular Diseases.

Further Reading Bale, T. L., Giordano, F. J. and Vale, W. W. (2003). A new role for corticotropin-releasing factor receptor-2: suppression of vascularization. Trends in Cardiovascular Medicine 13, 68–71. Bale, T. L. and Vale, W. W. (2004). CRF and CRF receptors: role in stress response and other behaviors. Annual Review of Pharmacology and Toxicology 44, 525–557. Coste, S. C., Quintos, R. F. and Stenzel-Poore, M. P. (2002). Corticotropin-releasing hormone-related peptides and receptors: emergent regulators of cardiovascular adaptations to stress. Trends in Cardiovascular Medicine 12, 176–182. Gravanis, A. and Margioris, A. N. (2005). The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Current Medicinal Chemistry 12, 1503–1512. Karalis, K., Muglia, L. J., Bae, D., et al. (1997). CRF and the immune system. Journal of Neuroimmunology 72, 131–136. Keller, P. A., Elfick, L., Garner, J., et al. (2000). Corticotropin releasing hormone: therapeutic implications and medicinal chemistry developments. Bioorganic & Medicinal Chemistry 8, 1213–1223. Makrigiannakis, A., Zoumakis, E., Kalantaridou, S., et al. (2003). Corticotropin-releasing hormone (CRF) and immunotolerance of the fetus. Biochemical Pharmacology 65, 917–921.

Corticotropin-Releasing Factor Receptors 641 Martinez, V., Wang, L., Million, M., et al. (2004). Urocortins and the regulation of gastrointestinal motor function and visceral pain. Peptides 10, 1733–1744. McCarthy, J. R., Heinrichs, S. C. and Grigoriadis, D. E. (1999). Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. Current Pharmaceutical Design 5, 289–315.

Slominski, A., Wortsman, J., Pisarchik, A., et al. (2001). Cutaneous expression of corticotropin-releasing hormone (CRF), urocortin, and CRF receptors. FASEB Journal 15, 1678–1693. Theoharides, T. C., Donelan, J. M., Papadopoulou, N., et al. (2004). Mast cells as targets of corticotropinreleasing factor and related peptides. Trends in Pharmacological Sciences 25, 563–568.

Corticotropin-Releasing Factor Receptors D E Grigoriadis Neurocrine Biosciences, Inc., San Diego, CA, USA ã 2007 Elsevier Inc. All rights reserved.

Hypothalamicpituitaryadrenal (HPA) axis

This article is a revision of the previous edition article by D E Grigoriadis, volume 1, pp 586–593, ã 2000, Elsevier Inc.

Introduction Corticotropin Releasing Factor Receptor Family Pharmacological Characteristics Distribution of Corticotropin Releasing Factor Receptor Subtypes Summary and Conclusion

Glossary Adenylate cyclase

Corticotropin releasing factor (CRF)

G-protein

G-proteincoupled receptor

One of the signaling molecules for G-protein-coupled receptors. On activation by a specific G-protein, this transmembrane protein either increases or decreases the rate of conversion of ATP to cAMP. A 41-amino-acid peptide primarily secreted by the hypothalamus into the hypophysial portal vasculature to act on the pituitary and cause the release of adrenocorticotropic hormone. A heterotrimeric protein that has high affinity for GTP and interacts with the cytoplasmic domains of a receptor, transducing the signal from the activated (ligand-bound) receptor to the secondmessenger signaling protein inside the cell. A protein that typically spans a cell membrane seven times with extracellular and intracellular loops coordinating the binding of a ligand outside the membrane with a signal transduction mechanism inside the membrane.

The hormonal pathway that is thought to mediate the primary stress response. CRF secreted from the hypothalamus acts on the anterior pituitary to release adrenocorticotropin (ACTH), which in turn acts on the adrenals to produce and release glucocorticoids. Glucocorticoids feed back to the pituitary to decrease ACTH release and also act on the hypothalamus to decrease CRF release in a negative feedback loop.

Introduction More than half a century ago, Geoffrey Harris first proposed the concept that the hypothalamus plays a primary role in the regulation of the pituitaryadrenocortical axis and extended the notion put forth by Walter B. Cannon that an organism’s ability to maintain homeostasis in the face of external stressors was coordinated by a specific portion of the central nervous system (CNS) operating in an automatic fashion. Subsequently, during the 1950s, Guillemin and Rosenberg and Saffran and Schally independently observed the presence of a factor in extracts of the hypothalamus that could stimulate the release of adrenocorticotropic hormone (ACTH, corticotropin) from anterior pituitary cells in vitro. This extract was termed corticotropin releasing factor (CRF). Although CRF was the first hypothalamic hypophysiotropic factor to be recognized, its chemical identity remained unknown largely due to the presence in hypothalamic extracts of other weaker secretagogues of ACTH secretion such as vasopressin, catecholamines, and angiotensin II. These agents, along with their synergistic effects with CRF on ACTH secretion and in combination with the relative lack of specificity of the in vitro bioassays, hindered the purification of this peptide. The development of radioimmunoassays for ACTH and quantitative