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Targeting mast cells in the treatment of functional gastrointestinal disorders
Targeting mast cells in the treatment of functional gastrointestinal disorders Javier Santos1, Carmen Alonso1, Mar Guilarte1,2, Marı´a Vicario1 and Juan Ramo´n Malagelada1 Enhanced knowledge of the pathophysiological basis of functional gastrointestinal disorders indicates that low-grade mucosal inflammation and mast cell hyperplasia are common findings. Mast cells are multipotent and mucosa-dwelling residents are uniquely located to communicate with host immune and nervous supersystems and with the gut microflora to provide tight microenvironmental conditions. Maintenance of homeostasis within this integrated defense system is crucial for symbiotic health, whereas breakdown of that balance might lead to uncontrolled mucosal and systemic inflammation. Numerous advances have recently emerged in the understanding of regulatory mechanisms of mast cell activation, development and homing to mucosal surfaces, as well as of the role of mast cells in key steps of mucosal inflammation. Such observations have stimulated the development of candidate drugs, such as tryptase or Syk inhibitors, that might be useful for the treatment of gastrointestinal functional disorders. Addresses 1 Digestive Diseases Research Unit, Department of Gastroenterology, Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, 08035 Barcelona, Spain 2 Allergy Unit, Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, 08035 Barcelona, Spain Corresponding author: Santos, Javier ([email protected]) Current Opinion in Pharmacology 2006, 6:541–546 This review comes from a themed issue on Gastrointestinal Edited by Jackie Wood Available online 7th September 2006 1471-4892/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2006.08.001
Introduction Despite being the most frequent cause for digestive consultation, functional gastrointestinal disorders have been paid little scientific attention for decades. The recently released Rome III classification for functional gastrointestinal disorders includes 28 adult and 17 pediatric entities [1]. Because of common symptomatic overlap among these disorders and the lack of information on the underlying mechanisms in many of them, here we focus on the two most well-studied and representative entities: functional dyspepsia and, mainly, irritable bowel syndrome (IBS). www.sciencedirect.com
Functional dyspepsia and IBS share physiopathological abnormalities, including visceral hypersensitivity and altered motor reactivity in the context of distorted central and peripheral neuro-immune regulation, which might well explain some of the clinical manifestations. Although a variety of factors might influence the initiation, development and perpetuation of such abnormalities, psychosocial factors, such as life stress, anxiety or depression, genetic predisposition and gastrointestinal infections, appear to be robustly associated, both epidemiologically and mechanistically. Convincing evidence indicates that mast cells (MCs) participate in the modulation of a wide variety of gastrointestinal physiological and pathological processes, including the regulation of epithelial barrier, mucosal immune function and host bacterial defense, motility and visceral sensitivity [2]. In IBS, synaptic-like contacts between MCs and enteric nerve fibers have been detected in the colonic mucosa, as well as increased MC numbers and MC products in both the small bowel and colon [3]. This anatomical relationship provides a physical substrate for bidirectional communication between the central nervous system and the gut by which stress, luminal bacteria and other regulatory factors might influence gastrointestinal physiology and inflammation. The mediators and pathways responsible for MC hyperplasia and activation in the gastrointestinal mucosa of some patients with functional gastrointestinal disorders have not been defined. Although MCs might release their contents abruptly and massively, following antigen-induced activation via highaffinity receptors for IgE (FceRIs), most observations point towards a slower and probably more selective emptying of granule contents, piecemeal degranulation, as the predominant mechanism involved in the regulation of autoimmune and chronic inflammatory disorders [4]. The biological consequences of the activation and degranulation of MCs are extremely complex and diverse, providing multiple levels of pharmacological intervention (Figure 1). Yet, it is not clear whether prevention or stimulation of MC function and growth is, in the end, good or bad for the control of gastrointestinal inflammation and related clinical symptoms, although molecular [5] and phenotypic [6] characterization of human MCs in the gastrointestinal tract might help to demonstrate this role. Acknowledging these limitations, in this review, we focus only on the most promising and rational therapies Current Opinion in Pharmacology 2006, 6:541–546
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Figure 1
Pharmacological modulation of MC effects on the gastrointestinal mucosa. Three arbitrary levels of intervention can be envisaged. Some drugs might act at different levels or affect various processes within the same level. Moreover, effects of the same drug might be different depending on the microenvironment. Activation or inhibition of any of the processes might influence gastrointestinal physiology or pathophysiology.
directed to modulate MC effects on gastrointestinal physiology that might be applicable for common functional gastrointestinal disorders.
Targeting growth, development and migration of MCs Stem cell factor
Stem cell factor (SCF) promotes maturation, proliferation, survival, chemotaxis, activation and IgE-induced mediator release of MCs. Binding of SCF to the c-kit receptor initiates downstream biochemical events involving phosphatidylinositol 3 kinases (PI3K) and mitogenactivated protein kinases, phospholipase C (PLC) and SRC [7]. Although imatinib, a well-known inhibitor of ckit, is now available, it seems disproportionate to use this drug to modulate MCs in non-lethal disorders such as IBS or dyspepsia. IgE
Recent evidence indicates that IgE, in the absence of specific antigen, promotes MC adhesion, migration, survival, mediator synthesis and release, and downregulation of FceRIs [8]. The value of anti-IgE humanized monoclonal antibodies, such as omalizumab or TNX901, as MC-stabilizing agents observed in several clinical trials in patients with allergic asthma [9], along with their safety, makes them attractive for the modulation of MC reactivity in IBS. Transforming growth factor b1
Transforming growth factor b1 (TGFb1) is an immunoregulatory cytokine constitutively expressed in the human gut with increased expression in inflammatory conditions Current Opinion in Pharmacology 2006, 6:541–546
in association with pericryptal MCs [10]. In the presence of TGFb1, human MC growth and IgE-dependent mediator release are inhibited [11]. TGFb1 genotypes have not been shown to be different in IBS patients [12]. However, in a postinfectious animal model, persistent muscle hypercontractility was associated with increased expression of TGFb1 [13] promoting TGFb1 as a potential target to modulate MCs in IBS. MC homing in the human gastrointestinal tract is unexplored but remains a promising area of research in which integrins, addressins and other adhesion molecules seem to have a relevant role.
Targeting MC activation and secretion MC stabilizers
Cromolyn sodium, nedocromil sodium, lodoxamide tromethamine, pemirolast potassium and quercetin are drugs believed to act by primary inhibiting the release of MC mediators. Ketotifen, olopatadine, desloratadine and pyrilamine maleate might also stabilize MCs by blocking histamine H1 receptors. Cromolyn and nedocromil can also inhibit the synthesis of IgE antibodies by human B lymphocytes. Oral preparations of cromolyn and antihistaminics are widely available, whereas the other drugs are commonly used as topical formulations for asthma or allergic reactions. Clinical experience is only available for cromolyn. Several, relatively old, placebo-controlled or uncontrolled studies showed significant beneficial effects of this drug in the control of gastrointestinal manifestations of IBS, mainly diarrhea [14,15]. Despite these promising results, www.sciencedirect.com
Mast cells and irritable bowel Santos et al. 543
no further follow-up studies other than open positive observations, including author’s own clinical experience, have been done, although clinical trials might be underway. The ability of some flavonoids, such as quercetin, to inhibit both IgE-mediated and IgE-independent release of interleukin 6 (IL-6), IL-8 and tumor necrosis factor a (TNFa) [16] could make them useful for the treatment of IBS because elevate levels of proinflammatory cytokines have been recently described in these patients [17]. Membrane receptors and signaling protein kinase cascades
A key receptor for MC activation is the membrane-based high affinity IgE recptor, FceRI. Aggregation of FceRI by specific antigens promotes phosphorilation of LAT (adaptor molecule linker for activation of T cells) by Lyn and Syk tyrosine kinases. Subsequent activation of the mitogen-activated protein kinase pathway induces the generation of eicosanoids by PLA2 and cytokines by activation of transcription factors [18]. Syk phosphorilation activates PLCg1, which regulates intracellular calcium and protein kinase C activity leading to MC degranulation. Aerosolized antisense oligonucleotides to Syk have been shown to inhibit allergen-induced inflammation in rats [19], as well as anti-Syk non peptidic molecules [20]. In addition, Syk kinase inhibitors designed to interrupt the signal from the IgE receptor on MCs, preventing activation and mediator release, are being developed for the treatment of allergic inflammation. Blockade of mitogen-activated protein kinase with cytokine-suppressive anti-inflammatory drugs [21] could also have important benefits in MC-mediated inflammation. A complementary signaling pathway for FceRI involves a Fyn kinase-dependent phosphorilation of NTAL (non-T cell activation linker) leading to the activation of PI3K instead of PLCg1 [22]. PI3K seems to be responsible for maintenance, instead of initiation, of the calcium mobilization required for degranulation [23]. Several negative regulators of MC activation have been described. FcgRIIIB, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif (ITIM), has been shown to coaggregate with FceRI blocking FceRI-mediated reactivity in vivo [24]. Other ITIM-containing receptors that inhibit FceRI-mediated MC activation are Gp49B1, CR200R, CD300a, the myeloidassociated immunoglobulin-like receptor, the MC function-associated antigen and the paired Ig-like receptor B [25]. More recently, a new negative regulator of MC activation, RabGEF1, has been described, as well as its downstream effector pathways in FceRI-dependent MC activation [26]. All these negative regulators for MC www.sciencedirect.com
activation provide interesting targets for future pharmacological approaches. Another pathway for MC activation involves surface Gprotein-coupled receptors that show different initiation signals but finally converge in PI3K. Among others, the adenosine A3 (A3A) receptor has attracted considerable interest as a potential target for drugs against asthma or inflammation. The binding of adenosine induces amplification of FceRI and antigen-mediated degranulation exclusively via PI3K [27]. Moreover, release of adenosine from MC provides an important autocrine signal that maintains MC activation. Although some studies describe potential benefits when blocking other adenosine receptors, in vivo evaluation of A3A receptor antagonists in animal models has been hampered by the lack of potent antagonists. Recently, A3A receptor functionally humanized mice have been developed, thus providing important opportunities for pharmacological evaluation of the human A3A receptor antagonists in the future [28]. Corticotropin-releasing hormone (CRH) and related peptides are key molecules that mediate stress responses. In the gastrointestinal tract, the stress–MC axis is certainly involved in the regulation of epithelial, motor and visceral responses [2]. Human MCs synthesize both CRH and urocortin in response to IgE and express G proteincoupled CRH receptors (R1 and R2) [29]. Activation of these receptors leads to selective release of cytokines and other proinflammatory mediators. CRH antagonists have been shown to inhibit the effect of MC-mediated change in colonic epithelial physiology in animal models [30]. Moreover, peripheral administration of a-helical CRH, a non-selective CRH receptor antagonist, improved distension-induced gut motor changes and visceral perception in IBS patients [31]. Because differential, even opposite, roles for CRH receptors are being increasingly recognized [32], development of selective CRH receptor antagonists for human use appears a promising and exciting area of drug innovation in functional gastrointestinal disorders. Pharmacological inactivation of PI3K has been shown to impair MC degranulation and cytokine release in mice, and therefore could be used to identify new potential targets for therapeutic intervention in MC-related inflammation [33]. Among the surface antigens, anti-CD63 antibodies inhibit FceRI-mediated signal by impairing the PI3K pathway that is known to be essential for both degranulation and adhesion in a rodent model of allergic diseases [34]. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases. Toll-like receptors (TLRs) are a group of pattern-recognition receptors expressed in a large number of immune cells and have an essential role in the activation of the innate immune response to microbial pathogens. MCs Current Opinion in Pharmacology 2006, 6:541–546
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have been shown to express these transmembrane receptors. Particularly, stimulation of cord-blood-derived human MCs with lipopolysaccharide or peptidoglycan leads to the release of inflammatory mediators through interactions with TLR4 and with TLR2, respectively [35]. These findings provide evidence that TLRs are potential targets for therapeutic intervention in MCrelated diseases.
Targeting MC mediators MC mediators can be divided in two groups of those that are preformed or newly synthesized (Table 1). Because biological functions of MCs might rely on the released mediators, we will discuss only pharmacological approaches directed to modulate post-released effects of major mediators, particularly those that might be involved in the regulation of gastrointestinal pathophysiology. Tryptase and protease-activated receptors
Tryptase, the most abundant serin protease stored in human MCs, can signal cells via protease-activated receptors (PARs). These receptors are of particular interest in the gastrointestinal tract, where they can modulate enteric neurotransmission, secretion, motility, epithelial permeability, intestinal inflammation and visceral sensitivity [37,38]. In the gastrointestinal tract, four members of the PAR family have been described, although intestinal MCs express PAR1 and PAR2, and MC tryptase activates only PAR2. No PAR antagonists are so far available. There are several clinical trials running with tryptase inhibitors, most of them in preclinical phase [39], for asthma, allergic disorders and inflammatory bowel disease, indicating that tryptase is a highly compelling target for the control of mucosal inflammation. Chymase
Chymase, another multifunctional effect serine-like protease mainly secreted from submucosal MCs, is involved in tissue structural remodeling and degradation of the extracellular matrix, and in vascular and epithelial permeability. In mice, some chymases are regulated by TGFb1. Reducing chymase availability with the MC stabilizer
tranilast has been demonstrated effective in animal models [40] but not in human clinical trials [41]. Development of new chymase inhibitors might proof valuable to counteract MC-mediated remodelation of submucosal structures in the inflamed intestine [42]. Histamine
MCs are the main source of histamine in the human intestine. In the intestine, histamine exerts relevant paracrine functions in the regulation of epithelial permeability, intestinal motility and secretion, and visceral nociception acting on cell-surface receptors. Although many selective antagonists for histamine receptors are available, they have not been properly evaluated for the treatment of functional gastrointestinal disorders. Recent evidence showing altered expression of histamine H1 and H2 receptor subtypes in mucosal biopsies from distal gut mucosa of IBS [43] makes these receptors even more attractive for future studies. Other mediators
Although serotonin is mainly produced by enterochomaffin cells, intestinal MCs are also able to release it. Serotonin exerts a variety of effects on intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells by regulating motility, vascular tone, secretion and perception. Two major serotonin receptors — 5hydroxytryptamine 3 (5-HT3) and 5-HT4 receptors — have been targeted for the treatment of IBS by using 5HT3 receptor antagonists (e.g. ondansetron, granisetron, alosetron and cilansetron), 5-HT4 receptor agonists (e.g. tegaserod), and renzapride, which is a full 5-HT4 agonist and a partial 5-HT3 antagonist [44]. Selective cholecystokinin and neurokinin receptor antagonists are also being developed as target receptors in the gastrointestinal system to increase gastric emptying and intestinal motility and to modulate intestinal sensitivity. Other relevant mediators released from MCs in appreciable amounts are nerve growth factor, TNFa and several
Table 1 Human intestinal MC mediators [36]. Preformed mediators: Histamine, tryptase, chymase, heparin, carboxipeptidase A, IL-8, TNFa, SCF, VEGF, 5-HT. Newly synthesized mediators: Lipid-derived mediators: PGD2, LTC4, LTD4, PAF. Cytokines and growth factors: IL-1b, IL-3, IL-4,IL-5, IL-6, IL-9, IL-13, IL-16,IL-18, TGFb, GM-CSF. Chemokines: MCP-1, MIP-1a, MIP-1b, RANTES, NGF, eotaxin. Neuropeptides: CRH, urocortin, substance P. Abbreviations: 5-HT, serotonin; CRH; corticotropin releasing hormone; GM-CSF, granulocyte macrophage colony stimulating factor; LT, leukotriene; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; NGF, nerve growth factor; PAF, platelet-activating factor; PG, prostaglandin; RANTES, regulated upon activation, normal T cell expressed and presumable secreted; SCF, stem cell factor; TGF, transforming growing factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
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chemokines. Although these molecules might undoubtedly contribute to MC-mediated regulation of gastrointestinal physiology, at this moment, their development as targets for IBS or dyspepsia either seems inadequate or is just emerging.
Conclusions Increasing incidence of functional gastrointestinal disorders along with growing awareness of the involved pathophysiological mechanisms is generating strong interest for both basic and clinical scientists, and pharmaceutical companies. In particular, one hot area of interest focuses on the study of MCs as targets for the development of new and helpful therapeutic agents aimed not only at controlling symptoms but also at preventing MC-related mucosal inflammation.
Acknowledgements Supported in part by the Spanish Ministry of Sanidad y Consumo, Subdireccio´n General de Investigacio´n Sanitaria, Instituto Carlos III, Fondo de Investigacio´n Sanitaria. J Santos (F.I.S. 01/3134 and F.I.S. 02/0190), C Alonso (CM04/00019) and M Vicario (CD05/00060) were the recipients of these grants.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1.
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35. Varadaradjalou S, Feger F, Thieblemont N, Hamouda NB, Pleau JM, Dy M, Arock M: Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur J Immunol 2003, 33:899-906. 36. Sellge G, Bischoff SC: Isolation, culture and characterization of intestinal mast cells. In Mast cells. Methods and protocols. Edited by Krishnaswamy G, Chi DS. Humana Press; 2006: 123-138. 37. Vergnolle N: Clinical relevance of proteinase activated receptors (PARs) in the gut. Gut 2005, 54:867-874. An interesting review to improve our understanding of the relevance of PARs in the regulation of gastrointestinal physiology. 38. Jacob C, Yang PC, Darmoul D, Amadesi S, Saito T, Cottrell GS, Coelho AM, Singh P, Grady EF, Perdue M, Bunnett NW: Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and b-arrestins. J Biol Chem 2005, 280:31936-31948.
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Introduction Despite being the most frequent cause for digestive consultation, functional gastrointestinal disorders have been paid little scientific attention for decades. The recently released Rome III classification for functional gastrointestinal disorders includes 28 adult and 17 pediatric entities [1]. Because of common symptomatic overlap among these disorders and the lack of information on the underlying mechanisms in many of them, here we focus on the two most well-studied and representative entities: functional dyspepsia and, mainly, irritable bowel syndrome (IBS). www.sciencedirect.com
Functional dyspepsia and IBS share physiopathological abnormalities, including visceral hypersensitivity and altered motor reactivity in the context of distorted central and peripheral neuro-immune regulation, which might well explain some of the clinical manifestations. Although a variety of factors might influence the initiation, development and perpetuation of such abnormalities, psychosocial factors, such as life stress, anxiety or depression, genetic predisposition and gastrointestinal infections, appear to be robustly associated, both epidemiologically and mechanistically. Convincing evidence indicates that mast cells (MCs) participate in the modulation of a wide variety of gastrointestinal physiological and pathological processes, including the regulation of epithelial barrier, mucosal immune function and host bacterial defense, motility and visceral sensitivity [2]. In IBS, synaptic-like contacts between MCs and enteric nerve fibers have been detected in the colonic mucosa, as well as increased MC numbers and MC products in both the small bowel and colon [3]. This anatomical relationship provides a physical substrate for bidirectional communication between the central nervous system and the gut by which stress, luminal bacteria and other regulatory factors might influence gastrointestinal physiology and inflammation. The mediators and pathways responsible for MC hyperplasia and activation in the gastrointestinal mucosa of some patients with functional gastrointestinal disorders have not been defined. Although MCs might release their contents abruptly and massively, following antigen-induced activation via highaffinity receptors for IgE (FceRIs), most observations point towards a slower and probably more selective emptying of granule contents, piecemeal degranulation, as the predominant mechanism involved in the regulation of autoimmune and chronic inflammatory disorders [4]. The biological consequences of the activation and degranulation of MCs are extremely complex and diverse, providing multiple levels of pharmacological intervention (Figure 1). Yet, it is not clear whether prevention or stimulation of MC function and growth is, in the end, good or bad for the control of gastrointestinal inflammation and related clinical symptoms, although molecular [5] and phenotypic [6] characterization of human MCs in the gastrointestinal tract might help to demonstrate this role. Acknowledging these limitations, in this review, we focus only on the most promising and rational therapies Current Opinion in Pharmacology 2006, 6:541–546
542 Immunomodulation
Figure 1
Pharmacological modulation of MC effects on the gastrointestinal mucosa. Three arbitrary levels of intervention can be envisaged. Some drugs might act at different levels or affect various processes within the same level. Moreover, effects of the same drug might be different depending on the microenvironment. Activation or inhibition of any of the processes might influence gastrointestinal physiology or pathophysiology.
directed to modulate MC effects on gastrointestinal physiology that might be applicable for common functional gastrointestinal disorders.
Targeting growth, development and migration of MCs Stem cell factor
Stem cell factor (SCF) promotes maturation, proliferation, survival, chemotaxis, activation and IgE-induced mediator release of MCs. Binding of SCF to the c-kit receptor initiates downstream biochemical events involving phosphatidylinositol 3 kinases (PI3K) and mitogenactivated protein kinases, phospholipase C (PLC) and SRC [7]. Although imatinib, a well-known inhibitor of ckit, is now available, it seems disproportionate to use this drug to modulate MCs in non-lethal disorders such as IBS or dyspepsia. IgE
Recent evidence indicates that IgE, in the absence of specific antigen, promotes MC adhesion, migration, survival, mediator synthesis and release, and downregulation of FceRIs [8]. The value of anti-IgE humanized monoclonal antibodies, such as omalizumab or TNX901, as MC-stabilizing agents observed in several clinical trials in patients with allergic asthma [9], along with their safety, makes them attractive for the modulation of MC reactivity in IBS. Transforming growth factor b1
Transforming growth factor b1 (TGFb1) is an immunoregulatory cytokine constitutively expressed in the human gut with increased expression in inflammatory conditions Current Opinion in Pharmacology 2006, 6:541–546
in association with pericryptal MCs [10]. In the presence of TGFb1, human MC growth and IgE-dependent mediator release are inhibited [11]. TGFb1 genotypes have not been shown to be different in IBS patients [12]. However, in a postinfectious animal model, persistent muscle hypercontractility was associated with increased expression of TGFb1 [13] promoting TGFb1 as a potential target to modulate MCs in IBS. MC homing in the human gastrointestinal tract is unexplored but remains a promising area of research in which integrins, addressins and other adhesion molecules seem to have a relevant role.
Targeting MC activation and secretion MC stabilizers
Cromolyn sodium, nedocromil sodium, lodoxamide tromethamine, pemirolast potassium and quercetin are drugs believed to act by primary inhibiting the release of MC mediators. Ketotifen, olopatadine, desloratadine and pyrilamine maleate might also stabilize MCs by blocking histamine H1 receptors. Cromolyn and nedocromil can also inhibit the synthesis of IgE antibodies by human B lymphocytes. Oral preparations of cromolyn and antihistaminics are widely available, whereas the other drugs are commonly used as topical formulations for asthma or allergic reactions. Clinical experience is only available for cromolyn. Several, relatively old, placebo-controlled or uncontrolled studies showed significant beneficial effects of this drug in the control of gastrointestinal manifestations of IBS, mainly diarrhea [14,15]. Despite these promising results, www.sciencedirect.com
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no further follow-up studies other than open positive observations, including author’s own clinical experience, have been done, although clinical trials might be underway. The ability of some flavonoids, such as quercetin, to inhibit both IgE-mediated and IgE-independent release of interleukin 6 (IL-6), IL-8 and tumor necrosis factor a (TNFa) [16] could make them useful for the treatment of IBS because elevate levels of proinflammatory cytokines have been recently described in these patients [17]. Membrane receptors and signaling protein kinase cascades
A key receptor for MC activation is the membrane-based high affinity IgE recptor, FceRI. Aggregation of FceRI by specific antigens promotes phosphorilation of LAT (adaptor molecule linker for activation of T cells) by Lyn and Syk tyrosine kinases. Subsequent activation of the mitogen-activated protein kinase pathway induces the generation of eicosanoids by PLA2 and cytokines by activation of transcription factors [18]. Syk phosphorilation activates PLCg1, which regulates intracellular calcium and protein kinase C activity leading to MC degranulation. Aerosolized antisense oligonucleotides to Syk have been shown to inhibit allergen-induced inflammation in rats [19], as well as anti-Syk non peptidic molecules [20]. In addition, Syk kinase inhibitors designed to interrupt the signal from the IgE receptor on MCs, preventing activation and mediator release, are being developed for the treatment of allergic inflammation. Blockade of mitogen-activated protein kinase with cytokine-suppressive anti-inflammatory drugs [21] could also have important benefits in MC-mediated inflammation. A complementary signaling pathway for FceRI involves a Fyn kinase-dependent phosphorilation of NTAL (non-T cell activation linker) leading to the activation of PI3K instead of PLCg1 [22]. PI3K seems to be responsible for maintenance, instead of initiation, of the calcium mobilization required for degranulation [23]. Several negative regulators of MC activation have been described. FcgRIIIB, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif (ITIM), has been shown to coaggregate with FceRI blocking FceRI-mediated reactivity in vivo [24]. Other ITIM-containing receptors that inhibit FceRI-mediated MC activation are Gp49B1, CR200R, CD300a, the myeloidassociated immunoglobulin-like receptor, the MC function-associated antigen and the paired Ig-like receptor B [25]. More recently, a new negative regulator of MC activation, RabGEF1, has been described, as well as its downstream effector pathways in FceRI-dependent MC activation [26]. All these negative regulators for MC www.sciencedirect.com
activation provide interesting targets for future pharmacological approaches. Another pathway for MC activation involves surface Gprotein-coupled receptors that show different initiation signals but finally converge in PI3K. Among others, the adenosine A3 (A3A) receptor has attracted considerable interest as a potential target for drugs against asthma or inflammation. The binding of adenosine induces amplification of FceRI and antigen-mediated degranulation exclusively via PI3K [27]. Moreover, release of adenosine from MC provides an important autocrine signal that maintains MC activation. Although some studies describe potential benefits when blocking other adenosine receptors, in vivo evaluation of A3A receptor antagonists in animal models has been hampered by the lack of potent antagonists. Recently, A3A receptor functionally humanized mice have been developed, thus providing important opportunities for pharmacological evaluation of the human A3A receptor antagonists in the future [28]. Corticotropin-releasing hormone (CRH) and related peptides are key molecules that mediate stress responses. In the gastrointestinal tract, the stress–MC axis is certainly involved in the regulation of epithelial, motor and visceral responses [2]. Human MCs synthesize both CRH and urocortin in response to IgE and express G proteincoupled CRH receptors (R1 and R2) [29]. Activation of these receptors leads to selective release of cytokines and other proinflammatory mediators. CRH antagonists have been shown to inhibit the effect of MC-mediated change in colonic epithelial physiology in animal models [30]. Moreover, peripheral administration of a-helical CRH, a non-selective CRH receptor antagonist, improved distension-induced gut motor changes and visceral perception in IBS patients [31]. Because differential, even opposite, roles for CRH receptors are being increasingly recognized [32], development of selective CRH receptor antagonists for human use appears a promising and exciting area of drug innovation in functional gastrointestinal disorders. Pharmacological inactivation of PI3K has been shown to impair MC degranulation and cytokine release in mice, and therefore could be used to identify new potential targets for therapeutic intervention in MC-related inflammation [33]. Among the surface antigens, anti-CD63 antibodies inhibit FceRI-mediated signal by impairing the PI3K pathway that is known to be essential for both degranulation and adhesion in a rodent model of allergic diseases [34]. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases. Toll-like receptors (TLRs) are a group of pattern-recognition receptors expressed in a large number of immune cells and have an essential role in the activation of the innate immune response to microbial pathogens. MCs Current Opinion in Pharmacology 2006, 6:541–546
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have been shown to express these transmembrane receptors. Particularly, stimulation of cord-blood-derived human MCs with lipopolysaccharide or peptidoglycan leads to the release of inflammatory mediators through interactions with TLR4 and with TLR2, respectively [35]. These findings provide evidence that TLRs are potential targets for therapeutic intervention in MCrelated diseases.
Targeting MC mediators MC mediators can be divided in two groups of those that are preformed or newly synthesized (Table 1). Because biological functions of MCs might rely on the released mediators, we will discuss only pharmacological approaches directed to modulate post-released effects of major mediators, particularly those that might be involved in the regulation of gastrointestinal pathophysiology. Tryptase and protease-activated receptors
Tryptase, the most abundant serin protease stored in human MCs, can signal cells via protease-activated receptors (PARs). These receptors are of particular interest in the gastrointestinal tract, where they can modulate enteric neurotransmission, secretion, motility, epithelial permeability, intestinal inflammation and visceral sensitivity [37,38]. In the gastrointestinal tract, four members of the PAR family have been described, although intestinal MCs express PAR1 and PAR2, and MC tryptase activates only PAR2. No PAR antagonists are so far available. There are several clinical trials running with tryptase inhibitors, most of them in preclinical phase [39], for asthma, allergic disorders and inflammatory bowel disease, indicating that tryptase is a highly compelling target for the control of mucosal inflammation. Chymase
Chymase, another multifunctional effect serine-like protease mainly secreted from submucosal MCs, is involved in tissue structural remodeling and degradation of the extracellular matrix, and in vascular and epithelial permeability. In mice, some chymases are regulated by TGFb1. Reducing chymase availability with the MC stabilizer
tranilast has been demonstrated effective in animal models [40] but not in human clinical trials [41]. Development of new chymase inhibitors might proof valuable to counteract MC-mediated remodelation of submucosal structures in the inflamed intestine [42]. Histamine
MCs are the main source of histamine in the human intestine. In the intestine, histamine exerts relevant paracrine functions in the regulation of epithelial permeability, intestinal motility and secretion, and visceral nociception acting on cell-surface receptors. Although many selective antagonists for histamine receptors are available, they have not been properly evaluated for the treatment of functional gastrointestinal disorders. Recent evidence showing altered expression of histamine H1 and H2 receptor subtypes in mucosal biopsies from distal gut mucosa of IBS [43] makes these receptors even more attractive for future studies. Other mediators
Although serotonin is mainly produced by enterochomaffin cells, intestinal MCs are also able to release it. Serotonin exerts a variety of effects on intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells by regulating motility, vascular tone, secretion and perception. Two major serotonin receptors — 5hydroxytryptamine 3 (5-HT3) and 5-HT4 receptors — have been targeted for the treatment of IBS by using 5HT3 receptor antagonists (e.g. ondansetron, granisetron, alosetron and cilansetron), 5-HT4 receptor agonists (e.g. tegaserod), and renzapride, which is a full 5-HT4 agonist and a partial 5-HT3 antagonist [44]. Selective cholecystokinin and neurokinin receptor antagonists are also being developed as target receptors in the gastrointestinal system to increase gastric emptying and intestinal motility and to modulate intestinal sensitivity. Other relevant mediators released from MCs in appreciable amounts are nerve growth factor, TNFa and several
Table 1 Human intestinal MC mediators [36]. Preformed mediators: Histamine, tryptase, chymase, heparin, carboxipeptidase A, IL-8, TNFa, SCF, VEGF, 5-HT. Newly synthesized mediators: Lipid-derived mediators: PGD2, LTC4, LTD4, PAF. Cytokines and growth factors: IL-1b, IL-3, IL-4,IL-5, IL-6, IL-9, IL-13, IL-16,IL-18, TGFb, GM-CSF. Chemokines: MCP-1, MIP-1a, MIP-1b, RANTES, NGF, eotaxin. Neuropeptides: CRH, urocortin, substance P. Abbreviations: 5-HT, serotonin; CRH; corticotropin releasing hormone; GM-CSF, granulocyte macrophage colony stimulating factor; LT, leukotriene; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; NGF, nerve growth factor; PAF, platelet-activating factor; PG, prostaglandin; RANTES, regulated upon activation, normal T cell expressed and presumable secreted; SCF, stem cell factor; TGF, transforming growing factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
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chemokines. Although these molecules might undoubtedly contribute to MC-mediated regulation of gastrointestinal physiology, at this moment, their development as targets for IBS or dyspepsia either seems inadequate or is just emerging.
Conclusions Increasing incidence of functional gastrointestinal disorders along with growing awareness of the involved pathophysiological mechanisms is generating strong interest for both basic and clinical scientists, and pharmaceutical companies. In particular, one hot area of interest focuses on the study of MCs as targets for the development of new and helpful therapeutic agents aimed not only at controlling symptoms but also at preventing MC-related mucosal inflammation.
Acknowledgements Supported in part by the Spanish Ministry of Sanidad y Consumo, Subdireccio´n General de Investigacio´n Sanitaria, Instituto Carlos III, Fondo de Investigacio´n Sanitaria. J Santos (F.I.S. 01/3134 and F.I.S. 02/0190), C Alonso (CM04/00019) and M Vicario (CD05/00060) were the recipients of these grants.
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