Current Pharmaceutical Design - Volume 17, Issue 34, 2011

Since the times of P. Ehrlich, F. D. von Recklinghausen, and O.Westphal, the research on mast cells and basophils made significant progression towards the recognition of their involvement in antimicrobial functions and of their role in mobilizing inflammation in wound healing, allergy, and autoimmunity. However, the role of mast cells in normal physiology is still poorly understood. Only in recent years, these cells are increasingly recognized as important effectors in number of pathways related mostly to tissue remodeling. The mast cells are capable to orchestrate inflammatory reactions and angiogenesis, they are frequently present near pre-neoplastic epithelial cells, etc. Absolute mast cell deficiency, as in the cross of Min mice to the C57BL/6-KitWsh/Wsh mice, can have overreaching immunological consequences.

Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local renin-angiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.

Cancer microenvironment is increasingly recognized as an important factor affecting cancer onset and progression. Since Wirchow reported in 1863 that tumors contain inflammatory cells, the field shifted significantly forward, and immune cells residing in tumors appear to be attractive targets of cancer therapies. For some methods, such as stem/progenitor cell isolation from both cancer and healthy tissues, removal of contaminating immune cells is crucial to achieve consistent, reproducible and accurate results. Despite current methods of lineage negative selection accounts for removal of over 99 % of immune cells from stem/progenitor cell isolates, the vast majority of lineage antibody cocktails retain basophils, dendritic cells, and mast cells. Here we discuss the ability of the most commonly used lineage markers to bind to the plasma membrane of mast cells and/or basophils, and suggest alternatives, which may be used for negative selection of these cellular populations. Both, mast cells and basophils, were shown to participate actively in cancer-associated angiogenesis, tissue remodeling and recruitment of other immune cell types, including eosinophils, B cells, memory T cells and Treg cells. In turn, tumor-derived peptides and chemotactic factors are known to recruit and activate mast cells in neoplasias, resulting in altered tumor progression. Repeated findings of CD34+ populations of mast cells and basophils further highlight necessity of their separation from stem/progenitor cell isolates in both, preclinical experiments and clinical praxis

Mast cells are largely found at interfaces between the environment and the internal milieu. Early knowledge of the mast cell suggested a role predominantly associated with allergy and pathologic response to antigens, but more recent research has shown a myriad of functions is likely. Wound healing is a complex process of lysis and reconstitution controlled by a series of cell signalling proteins. Mast cells have been shown to play a significant role in the early inflammatory stage of wound healing and also influence proliferation and tissue remodelling in skin. Emerging work implicates the mast cell as a modulator of intestinal healing particularly following surgical anastomosis. The study of mast cells and wound healing involves the use of cell studies and animal models through the use of mast cell inhibitors, promoters and mast cell deficient rodent strains. This review addresses wound healing in skin and the gastrointestinal tract and specifically identifies data pertaining to the role of the mast cell in the process of cell breakdown, repair and regeneration

Interleukin-19 (IL-19) is a member of the IL-10 family of cytokines. The last ten years from the finding of IL-19, investigations underline the role of IL-19 in the immunological diseases. It is known that expression of IL-19 is increased in the epidermis of patients with psoriasis, which is a Th1 dominant disease. Increased concentration of IL-19 has also been found in the serum of patients with asthma, which is a Th2 dominant disease. There is an increasing body of data demonstrating that IL-19 is associated with the pathogenesis of both Th1 and Th2 dominant diseases. Regarding the role of IL-19 on the innate immunity and inflammation, interestingly, in vitro studies have shown that lipopolysaccharide can stimulate human monocytes and macrophages to upregulate the expression of IL-19. IL- 19 is upregulated in macrophages after infection and lessens inflammation by suppressing the production of tumor necrosis factor-α, IL-6 and IL-12, but not by inducing IL-10. In addition, IL-19-deficient mice are susceptible to experimental colitis induced by dextran sodium sulfate, a disease which is characterized by excessive inflammatory responses of local macrophages and epithelial cells to intestinal microflora. In this review, we discuss our current understanding of the role of IL-19 in autoimmune and inflammatory diseases.

Polarization of naive T cells in a certain functional direction is influenced not only by antigen type and concentration, but also by co-stimulatory signals, the local cytokine environment and transcription factors that activate or inhibit specific T cell lineage programs through positive or negative feedback loops. Interleukin-25 (IL-25) is a recently identified member of the IL-17 cytokine family. It has the ability to influence innate and adaptative immunity. Within the IL-17 family, IL-25 possesses the lowest degree of homology to IL- 17A, does not share common biological functions with other members of the IL-17 cytokine family, and instead has been been implicated in the promotion of Th2 immunity. IL-25 drives the expression of IL-4, IL-5, and IL-13, thereby contributing to allergic disease. Although our understanding of the biology of IL-25 is increasing, how IL-25 is regulated is still poor. On the other hand, recent studies have shown a novel anti-inflammatory role for IL-25 as a key factor in the attenuation of IL-17-mediated inflammation, such as in colitis, encephalomyelitis, and diabetes mellitus. Thus, IL-25 and IL-17, being members of the same cytokine family, seem to play opposing roles in the pathogenesis of autoimmune diseases. In this article, we review the dual roles of IL-25 in immune responses, the molecular basis for these effects, and the potential therapeutic implications.

Introduction of flow cytometric technique to the research on basophil activation has led to significant achievements in allergy diagnosis in vitro. Most of the studies employing the flow cytometry used CD63 as a marker of basophil activation and only some of them used CD203c. Recently discovered basophil activation markers, including CD164, opened new possibilities for solving majority of current diagnostic needs. Use of allergen-induced CD164 upregulation in diagnosis of pollen allergy has been validated, and this encourages to further studies on other diagnostic usefulness of this marker. There are some hopeful data indicating that it might be useful in diagnosis of allergy caused by variety of other allergens, including drug allergens. Although CD164 upregulation as a marker of basophil activation is a promising and powerful diagnostic tool, it still requires a lot of both basic research and comparative studies with older and well known markers, in order to select the best of them. A research on basophil CD164 upregulation caused by various stimuli offers a good possibility to increase our knowledge of basophil's involvement in allergic inflammation. Moreover, this might trigger a variety of pharmacological studies with known and new anti-inflammatory drugs in the future.

In addition to being major effector cells in the elicitation of allergic responses, mast cells have been found to play a significant role in the establishment of innate and adaptive immune responses. This occurs, in part, by regulating the phenotype and function of immune cells such as T cells, B cells and dendritic cells, and by acting as antigen presenting cells. Indeed, mast cells have been found to be activated in various T cell-mediated inflammatory processes and to reside in close physical proximity to T cells. Such observations have led investigators to propose a functional relationship between these two cell populations. Mast cells can interact with other cells including T cells in several ways such as cell-cell interaction via membrane associated receptors, release of cytokines and chemokines or by heterotypic adhesion to activated T cells. In this review, we focus on a novel communication pathway between mast cells and other inflammatory cells that occurs by the release of or response to membrane vesicles. Membrane vesicles are circular fragments, released from the endosomal compartment as exosomes or shed from the cell plasma membrane as microparticles. Because their membrane orientation is the same as that of the donor cell, they can be considered to be miniature versions of a cell. Growing evidence indicates that microparticles play a pivotal role in cell to cell communication. The functional consequences of such membrane transfers include the induction, amplification and/or modulation of immune responses, as well as the acquisition of new functional properties by recipient cells.

The three heavy metals, mercury, gold and silver commonly and specifically induce aberrant immunological responses leading to autoimmune disorders in genetically susceptible animals and humans. The disorders are characterized by autoantibody production, increases in serum IgG and IgE, polyclonal activation of B and T lymphocytes and renal immune complex deposition and glomerulonephritis. Mast cells play key roles in allergic and inflammatory reactions. A growing body of evidence suggests that mast cells are key players in innate and adaptive immunity and involved in autoimmune diseases. Mast cells are also direct targets for autoimmunity-inducing metals both in vitro and in vivo and play a role in the development of metal-induced autoimmune disorders. The three metals specifically modulate mast cell function, including degranulation and secretion of arachidonic acid metabolites and cytokines such as interleukin-4. Divergent signaling components, including mitogen-activated protein kinase activation, reactive oxygen and nitric oxide generation and Ca2+ influx are modulated by the metals. Furthermore, the metals have considerable impacts on mast cell survival, which also species seems to be involved in the development of metal-induced autoimmune disorders. In this review, we provide an overview of recent advances in our understanding of the impacts of the three metals on mast cell signaling, function and survival and their possible roles in the pathologies of metal-induced autoimmunity.

It is well established that mast cells play a key regulatory role in allergy and inflammation involving engagement of antigen with IgE bound to high-affinity IgE receptors (Fc??RI). The most aggressive efforts in regulating mast cell function have focused on selectively inhibiting cell activation and subsequent mediator synthesis and release, or alternatively, blocking the action of proinflammatory mediators in order to prevent or reduce disease severity. More recently, the goal for rationally designed pharmacotherapy has shifted focus to targeting and disrupting signaling pathways leading to inhibition of specific cell function(s). In this context, the PI-3K/PIP3/Akt pathway represents a potent target for pharmacologic intervention in mast cell-mediated inflammatory disorders. A pivotal component of this cascade is the activation of phosphatidylinositol-3-kinase (PI-3K) leading to a rise in intracellular levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 has broad effects on mast cell signaling and function as well as on proliferation and survival. We propose that PIP3 represents a potent target for developing therapeutic approaches to down regulate mast cell function and, in turn, reduce the severity of mast cell dependent disease. In this article we review approaches that have been taken to regulate the PI-3K pathway in mast cells. Moreover, we review a novel approach to target the signaling lipid, PIP3, and deplete intracellular levels of this phosphoinositol using a chimeric toxin composed of the Fc??RI binding region of IgE and the active subunit of the cytolethal distending toxin, CdtB, which we have recently demonstrated to function as a PIP3 phosphatase.

Mast cells, the multi-functional secretory cells, are the pivotal effector cells in immune response, and contribute to the pathogenesis of many diverse diseases, like asthma and mastocytosis, by releasing numerous proinflammatory mediators. Pimecrolimus (SDZ ASM 981) is a derivative of the macrolactam ascomycin and is a member of the calcineurin inhibitor class of immunosuppressors. It inhibits the calcineurin-dependent activation of nuclear factor of activated T cells and the expression of a number of proinflammatory cytokines in turn. Pimecrolimus has high and selective anti-inflammatory activity within the skin, and with much lower potential to affect local and systemic immune responses. Therefore it has been widely used for treatment of various inflammatory skin diseases. It has a cellselective mode of action, and mast cells are its specific target cells. Pimecrolimus inhibits the release of both preformed and de novo synthesized mediators from activated mast cells and inhibits accumulation of mast cells by inducing apoptosis. Several experimental and clinical reports have demonstrated the successful application of pimecrolimus and other calcineurin inhibitors, such as tacrolimus and cyclosporine A, to treat mastocytosis, a spectrum of disorders characterized by mast cell hyperplasia, especially cutaneous mastocytosis. These new findings suggest that pimecrolimus and other calcineurin inhibitors may be a novel and effective therapeutic approach for mast cell-associated diseases such as asthma and mastocytosis.

Benzene is a carcinogenic compound used in industrial manufacturing and a common environmental pollutant mostly derived from vehicle emissions and cigarette smoke. Benzene exposure is associated with a variety of clinical conditions ranging from hematologic diseases to chronic lung disorders. Beside its direct toxicity, benzene exerts multiple effects after being converted to reactive metabolites such as hydroquinone and benzoquinone. Mast cells and basophils are primary effector cells involved in the development of respiratory allergies such as rhinitis and bronchial asthma and they play an important role in innate immunity. Benzene and its metabolites can influence mast cell and basophil responses either directly or by interfering with other cells, such as T cells, macrophages and monocytes, which are functionally connected to mast cells and basophils. Hydroquinone and benzoquinone inhibit the release of preformed mediators, leukotriene synthesis and cytokine production in human basophils stimulated by IgE- and non IgE-mediated agonists. Furthermore, these metabolites reduce IgE-mediated degranulation of mast cells and the development of allergic lung inflammation in rats. Both in vitro and in vivo studies indicate that benzene metabolites alter biochemical and functional activities of other immunocompetent cells and may impair immune responses in the lung. These inhibitory effects of benzene metabolites are primarily mediated by interference with early transduction signals such as PI3 kinase. Together, currently available studies indicate that benzene metabolites interfere by multiple mechanisms with the role of basophils and mast cells in innate immunity and in chronic inflammation in the lung.