Pio Conti | Università degli Studi "G. d'Annunzio" Chieti Pescara (original) (raw)
Papers by Pio Conti
Mast cells (MCs) are mediators of allergy and inflammation and participate in the growth of cance... more Mast cells (MCs) are mediators of allergy and inflammation and participate in the growth of cancer
cells. MCs can promote both neoangiogenesis and tumor growth. They increase in the stroma of certain
tumors where they can be recruited by tumor-derived chemoattractants, such as monocyte chemotactic
protein-1 (MCP-1), RANTES and stem cell factor (SCF) to selectively secrete inflammatory molecules
including chemical mediators and cytokines (TNF, IL-6 and IL-1). However, MC differentiation pathways
and heterogeneity in cancer are still poorly understood. Human interleukin 1 (IL-1) plays a pivotal role
in the pathogenesis of many diseases and functions, including host response to microbial invasion, injury
inflammatory processes, immunologic challenges and cancer. Inflammation around the tumor includes
the infiltration of mast cells and facilitates cancer growth. MCs are activated by IL-1 which can be
produced by certain cancer cells and stimulate the stromal cells to selectively release IL-6, contributing
to the development of Th-17 cells and increasing inflammation. IL-37, mainly generated by macrophage
cell line, is an IL-1 family member which binds IL-18 receptor α (IL-18Rα) chain, and acts as a natural
inhibitor of immune responses. IL-37 down-regulates cJun induced by IL-1, pro-inflammatory signals
and reduces the expression of the mitogen-activated protein kinase (MAPK) p38α, STAT transcription
factors and p53, affecting cellular differentiation and proliferation. In the present study we report the
relationship between inflammatory mast cells, cancer and the beneficial effect of IL-37.
Journal of biological regulators and homeostatic agents
Multidrug resistance (MDR) to anticancer chemotherapy is often mediated by the overexpression of ... more Multidrug resistance (MDR) to anticancer chemotherapy is often mediated by the overexpression of the plasma membrane drug transporter P-glycoprotein (Pgp) encoded by multidrug resistance gene (MDR1). Various chemosensitizing agents are able to inhibit Pgp activity but their clinical application is limited by their toxicity. Furthermore, hepatotoxicity related to chemotherapy causes delays of treatment in cancer patients and often requires supplementation of anti-tumour therapy with hepatoprotective agents. In this in vitro study, we investigated the effectiveness of an endogenous hepatoprotective agent, S-adenosylmethionine (SAMe), and a natural hepatoprotective compound, Cynarin (Cyn), to inhibit Pgp activity in order to evaluate their potential use as chemosensitizing agents. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) expressing high levels of Pgp were treated with two hepatoprotectors at various concentrations (1, 5 and 10 microM) that are clinically ac...
Cytokines are involved in the regulation of the immune system and clearly communicate with immune... more Cytokines are involved in the regulation of the immune system and clearly communicate with immune cells and bone cells. Therefore, cytokines are produced by many different cell types and are state. Cytokines such as IL-1, TNF, IL-6, TGF-b, IL-2, IL-8, M-CSF, IL-12, IL-18 and IFN-, and anti-resorption. The immune system and bone cells require positive and negative regulators to maintain homeostasis. In this article, we discuss the interactions between cytokines and bone cells in maintaining homeostasis of the bone. However, the relationship between intercellular signalling, osteoprogenitor cells, mature osteoblasts, osteocytes and osteoclasts, in regulating the pathophysiology of the bone, still remains to be elucidated. Editorial.
Endocrinology systems exert an important effect on vascular function and have direct actions on b... more Endocrinology systems exert an important effect on vascular function and have direct actions on blood vessels. Estrogens provoke an increase in skin elasticity, epidermal hydration, skin thickness, reduce skin wrinkles and augment the content of collagen and the level of vascularisation. Therefore, there is an intricate cross-talk between skin conditions and stress. In stress, β2-adrenoreceptor (β2AR) pathway, cortisol, epinephrine and norepinephrine increase DNA damage and interfere with the regulation of the cell cycle, contributing to aging and skin diseases. Substance P is a neuropeptide released in the skin from the peripheral nerve and is related to stress and inflammation. SP provokes infiltration of inflammatory cells in the skin and induces a variety of cytokines/chemokines. Corticotropin-releasing hormone (CRH), produced by mast cells, is a neuropeptide also expressed in skin and responds to stress. CRH initiates diverse intracellular signaling pathways, including cAMP, protein kinase C, and mitogen-activated protein kinases (MAPK). Under stress, CRH, glucocorticoids, epinephrine and cytokines are generated. Moreover, the release of ACTH binds the receptor MC2-R and stimulates the generation of glucocorticoids such as corticosterone and cortisol, which interact with the transcription factors AP-1 and NF-kB. In skin keratinocytes, ACTH promotes the generation of pro-inflammatory cytokines, which enhances T-cell activity. Cortisol is immunosuppressive by inhibiting Th1 and Th2 cell response, antigen presentation, antibody and cytokine/chemokine production. However, glucocorticoids are certainly helpful in Th1-mediated autoimmune disorders. On the other hand, cytokines, such as TNF, IL-1 and IL-6, stimulate the generation of CRH and activate HPA axis in inflammatory states. Here, we describe for the first time a cross-talk between endocrinology and skin, including pro-inflammatory cytokines and neurogenic inflammatory pathways.
Translational Research, 2009
Chemokines are cytokines with chemotactic properties on inflammatory cells and other cell types. ... more Chemokines are cytokines with chemotactic properties on inflammatory cells and other cell types. Chemokine (C-C motif) ligand 2 (CCL2), which is also called monocyte chemotactic protein 1 (MCP-1), is a potent chemotactic molecule that attracts lymphocytes, monocytes, mast cells, and memory T cells, but not neutrophils. CCL2/MCP-1 represents a link between the activation of monocytes, lymphocytes, basophils, mast cells, and eosinophils in inflammatory disorders, such as the late-phase allergic reaction. This C-C chemokine also plays a role in regulating Th-cell cytokine production and leukocyte trafficking. Laboratory of allergic diseases (LAD) cells is the first reported human mast cell line that closely resembles a primary culture of CD34+-derived human mast cells. These cells were cultured in vitro and treated with different concentrations of substance P (SP) for the production of CCL2/MCP-1. We used calcium ionophore as a positive control for stimulating transcription and translation of CCL2/MCP-1. The stimulation of SP on CCL2/MCP-1 was statistically significant (P < 0.05) compared with the control (untreated cells). In this study, we determined the expression and secretion of CCL2/MCP-1 from SP-activated LAD2 human mast cells in vitro. The levels of CCL2/MCP-1 from SP-activated LAD2 human mast cells were higher at 10 microM and at 18 h incubation compared with controls. This effect was also revealed on CCL2/MCP-1 messenger RNA (mRNA) expression, as determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Our data suggest that SP is an important neurotransmitter that can stimulate the chemokine CCL2, which plays a fundamental role in inflammation by recruiting inflammatory cells to specific cites.
Neurotoxicity Research, 2007
Lateral Sclerosis (ALS), Parkinsooism Dementia Complex, etc., and it causes extensive damage to t... more Lateral Sclerosis (ALS), Parkinsooism Dementia Complex, etc., and it causes extensive damage to the nervous system, including the impairment of learning and memory. However, to date, the mechanism of Al neurotoxicity has not been fully elucidated. Neuronal apoptosis has become a focus of interest, as it has been reported to play a key role in the impairment of learning and memory processes (Thompson, Science 267:1456, 1995). The Bcl-2 gene acts as an important effector for inhibiting apoptosis. In the present study we observe neuronal apoptosis in association with learning and memory impairment, as well as regional brain alterations in BcI-2 expression in rats chronically exposed to Al. The chronic Al-intoxicated model was established by i.p. injection of AICI3 in adult Sprague Dawley rats for 3 successive days, with one-day intervals, for 60 days. After exposure, the step-down test was performed to examine the behavioral reaction of the rats. Neuronal apoptosis and Bcl-2 protein expression in different regions of rat brain were then assessed by an immunohistochemical method. In the step-down test, the latency of Al-exposed rats was significantly lower than that of controls. Also, the num-ber of performance errors in 5 minutes of exposure was significantly higher than that of controls. Neuronal apoptosis was extensive in the brain of Al-exposed groups, and the expressions of Bcl-2 protein in frontal cortex, cerebellum and hippocampus of Al-exposed rats was stronger. In conclusion, chronic Al-exposure in rats is associated with neuronal apoptosis in brain, and impaired learning and memory. Augmented Bcl-2 protein expression may be a stimulated compensatory mechanism.
International Archives of Occupational and Environmental Health, 1999
The objective of this study was to analyze the role of some trace metals in the immune system of ... more The objective of this study was to analyze the role of some trace metals in the immune system of nonallergic or atopic men. One of these elements (Zn) is essential for immune function, whereas others, present in the urban environment, are known to be allergenic (Ni and Cr) or toxic (Pb). Serum levels of interleukin (IL) 2, 4, 5, and 13 and of interferon-y and immunoglobulins, blood lymphocyte subsets, blood concentrations of Pb and Zn, serum levels of Zn, and urinary Cr and Ni concentrations were determined in 17 nonallergic men (mean age 34 years) and 17 healthy nonsymptomatic atopic men living in urban areas. The mean blood concentration of Pb (a marker of exposure to toxic agents) was 11 microg/dl in both groups, which showed similar levels of blood Zn and of urinary Ni and Cr, whereas the serum Zn concentration was lower in the atopic group. Serum IgE levels were much higher in atopic men than in nonallergics, whereas serum IL-2, IL-5, and IL-13 concentrations were lower, possibly due to binding to tissue receptors and cells. Moreover, in atopic subjects, numbers of blood CD4+-CD45RO-"virgin" lymphocytes were significantly lower and the CD4+ -CD45RO+/CD4+ -CD45RO- ratio was more elevated, indicating an activation of the immune system. Serum IgE levels of atopic men, in contrast to those of nonallergic subjects, were correlated with CD19+ and CD5--CD19+ B lymphocytes. Blood Pb levels of both groups of men were correlated with CD4+, CD4+-CD45RO+, and HLA-DR+ [activated T-, B-, CO4+ -C. and natural killer (NK) cells] lymphocytes; in particular, blood Pb levels of the nonallergic men were also significantly correlated with CD25+ cells activated by IL-2, whereas those of the atopic men were also correlated with CD3--HLA-DR+ (B- and NK-cells) and CD5--CD19+ lymphocytes. Besides serum Zn levels, urinary Ni and Cr of nonallergic men were correlated with several immune parameters; in particular, urinary Cr was correlated with serum IL-5 and IgE and urinary Ni was correlated with CD4+ -CD45RO+ and CD3+ -CD25+ lymphocytes. This correlation of Ni and Cr, also found in previous studies in nonallergic subjects, confirms the hypothesis that these metals are involved in mechanisms of immune response regulation and that allergy to Ni or Cr represents an alteration of physiological mechanisms. Previous experimental studies have demonstrated that Pb exerts immunomodulatory effects on CD4+ and B- lymphocytes, enhancing the production of Th2-like cytokines and IgE. These experimental results confirm those of this study, showing in atopic men the correlation of B-lymphocytes with both blood Pb and serum IgE levels. This suggests that Pb may enhance the incidence of atopy in populations exposed to an urban environment.
Annals of clinical and laboratory science, 2003
Resveratrol, synthesized in dietary plants and contained in wine, has been reported to play a ben... more Resveratrol, synthesized in dietary plants and contained in wine, has been reported to play a beneficial role in certain cardiovascular regulatory mechanisms and to inhibit carcinogenesis by activating immune and inflammatory responses and apoptosis. The object of this study was to elucidate the "in vitro" effects of different concentrations of resveratrol (10(-4), 10(-5), and 10(-7) M) on human peripheral blood mononuclear cell (PBMC) proliferation and cytokine release. Spontaneous PBMC proliferation was unaffected by resveratrol, while the compound at 10(-4) M inhibited (69%) the PHA-stimulated PBMC proliferation. The proliferation stimulation index (ie, the ratio of PHA-stimulated PBMC proliferation/spontaneous PBMC proliferation) of cultures containing 10(-4) M resveratrol was very low in relation to the control, while the proliferation stimulation index values at 10(-5) and 10(-7) M were similar and slightly higher (without statistical significance), respectively. At ...
Neurotoxicity Research, 2009
Substance P (SP) is an important neuropeptide involved in neurogenic inflammation and most of its... more Substance P (SP) is an important neuropeptide involved in neurogenic inflammation and most of its pathophysiological functions are mediated through binding to the neurokinin-1 receptor. SP exerts various proinflammatory actions on immune-cells, including macrophages. Several compounds such as cytokines have the capacity to activate and stimulate macrophages to produce arachidonic acid oxygenation and lipoxygenation products. Leukotriene B4 (LTB4) is one of the most important mediators of leukocyte activation in acute and chronic inflammatory reactions. LTB4 stimulates chemotaxis, lysosomal enzyme release, and cell aggregation. In this report, we studied the effect of SP on rat adherent granuloma macrophages (RAGMs). The chronic granuloma in rat was induced by dorsal injections of a potassium permanganate (KMnO4) saturated crystal solution (200 microl of a 1:40 dilution). After 7 days, all rats developed a subcutaneous granuloma in the injection site from which infiltrated macrophages were extracted, isolated, and cultured in vitro. We tested the hypothesis that SP stimulates the production of LTB4 in RAGMs and increases lipoxygenase expression. Here we show that the cell-free supernatant of RAGMs stimulated with SP (10 microM), resulted in statistically significant increases of LTB4 Preincubation of RAGMs with NDGA (nordihydroguaiaretic acid (10 microM), completely abolished the production of LTB(4) in the supernatants and lipoxygenase expression on RAGMs challenged with SP, or the cation ionophore A23187 (positive control). Similar effects were obtained when the cells were pretreated with dexamethasone (10 microM). Our results suggest that SP is able to stimulate the release of LTB4 and lipoxygenase expression in macrophages from chronic inflammatory granuloma and provide further evidence for a neuroinflammatory pathway.
Cancer Immunology Immunotherapy, 1994
During the past decade, particular attention has been focused on treatment of bladder cancer pati... more During the past decade, particular attention has been focused on treatment of bladder cancer patients with the bacterial agent bacillus Calmette-Gu&in (BCG). In these studies, bladder cancer patients were instilled with BCG (75 rag/50 ml) once per week for 6 weeks, 1-2 weeks following trans-urethreal resection of the bladder. Cystoscopy was performed after 6 weeks and, unless tumor progression was present, monthly treatments were given for 1 year. Blood was drawn 2 h after the last instillation, and monocytes were isolated (5x 106 cells/ml) and treated, or not, with lipopolysaccharide (LPS) (20 gg/ml) for tumor necrosis factor a (TNFo~), interleukin-lo~ (IL-la) and interleukin-6 (IL-6) release. The levels of monokines were determined by a monokine-specific enzyme-linked immunosorbent assay. Our results clearly show that, after 18 h incubation, macrophages from BCG-treated bladder cancer patients produced from 2.8-to 1.9-fold and from 2.0-to 1.3-fold greater amounts of TNFo~ and IL-lc~ respectively, compared to macrophages from healthy controls, 5-fold higher than bladder cancer patients not treated with BCG. IL-6 was not affected. In another set of experiments macrophages (5x106 cells/ml) from healthy subjects were pretreated, or not, with BCG (100 gg/ml) overnight and treated, or not, with LPS 20 gg/ml alone and in combination with interleukin-1 receptor antagonist (IL-lra) 250 ng/ml. Macrophages treated with BCG had a strong stimulatory effect on IL-1 oc release (9.45 ng/ml) while LPS was less effective (3.59 ng/ml). The combination of BCG plus LPS produced an additive effect on IL-lo~ release (13.71 ng/ml) compared to the effect of the compound alone. The addition of IL-lra (250 ng/ml) to BCG was not effective, while when IL-lra was added to BCG plus LPS only a partial inhibition of IL-I~ release was found (9.83 ng/ml), compared to BCG plus LPS without IL-lra (13.71 ng/ml). These effects seem to be related to the inhibition of IL-lc~ stimulated with LPS, but not BCG. The priming effect of BCG exerted on LPS-stimulated monocyte production of TNFc~ and IL-1 o~ from bladder cancer patients led us to study the possible modulation of fibrinogen and C-reactive protein in the serum of BCGtreated cancer patients. The plasma levels of fibrinogen and C-reactive protein were higher (approximately twice) in BCG-treated patients compared to values obtained in untreated patients or healthy controls. We conclude that the beneficial immunotherapeutic effects of BCG in bladder cancer patients are related to its capacity to prime macrophages to enhance the release of TNFc~ and IL-I~, but not IL-6 in response to physiological secondary stimuli, or through the direct stimulation of BCG on IL-la or TNFo~ which are directly involved in the killing of cancer cells. Moreover, the increase of IL-lc~ or TNFc~ in BCG bladder cancer patients may lead to high plasma levels of fibrinogen and C-reactive protein, two proteins responsible for the acute-phase response.
Vitamin E is found in eight forms in nature which include four tocopherols (alpha, beta, gamma an... more Vitamin E is found in eight forms in nature which include four tocopherols (alpha, beta, gamma
and delta) and four tocotrianols (alpha, beta, gamma and delta). The classic effect of vitamin E is to
reduce and prevent oxygen damage to the tissue and is useful for the treatment of pain, inflammation
and allergic reactions. In addition to antioxidant activity, vitamin E also has a number of different and
related functions. It protects against cancer, improves immune response, lowers the incidence of infectious
diseases, cardiovascular diseases and is protective in allergy and asthma risk, and other disorders. Vitamin E increases n-6 polyunsaturated fatty acid (PUFA) and decreases n-3 PUFA, an effect that diminishes asthma and allergic diseases. Moreover, vitamin E regulates vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration through its oxidant and non-antioxidant effect. Furthermore, vitamin E modulates the endothelial function by altering VCAM-1-induced oxidative activation of endothelial cell PKCα. However, vitamin E is not consistently associated with asthma and/or allergy, and in some cases there are conflicting results on allergy and inflammatory diseases. The association of vitamin E and allergy appears to be very complex, and further study needs to clarify this dilemma.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2007
To investigate the association between plasma interleukin-18 (IL-18) levels and atherosclerosis i... more To investigate the association between plasma interleukin-18 (IL-18) levels and atherosclerosis in patients with obstructive obstructive sleep apnea hypopnea syndrome (OSAHS). Based on apnea hypopnea index (AHI) during sleep monitored by polysomnography, 52 male patients with OSAHS were recruited and divided into a mild OSAHS group (n = 16), a moderate group (n = 18), and a severe group (n = 18). Eighteen healthy subjects were selected as the control group. Twenty patients with moderate-to-severe OSAHS underwent continuous positive airway pressure (CPAP) treatment. HDL5000 color Doppler ultrasound was used to measure intima-media thickness (IMT) of the jugular arteries. Plasma IL-18 levels were measured by ELISA. Analysis of variance, paired-samples T test and Pearson correlation analysis were used for statistics. Compared with the plasma IL-18 levels in the control group [(250 +/- 76) ng/L], there was a significant increase in the mild OSAHS group [(352 +/- 76) ng/L], moderate grou...
Inflammation Research, 1990
Microglia derive from mononuclear myeloid progenitors and are a major glial complement of product... more Microglia derive from mononuclear myeloid progenitors and are a major glial complement of products are implicated in the neuronal destruction usually observed in various neurodegenerative diseases. Microglia cells express corticotropin releasing hormone (CRH) receptors, and activation of microglia by CRH releases bioactive molecules which have a biological effect in the brain and regulate several neurological diseases. CRH plays a pivotal role in stress responses and is a key mediator of the hypothalamic-pituitary-adrenocortical system. CRH is expressed in human mast cells, leading to and act synergistically to increase vascular permeability. CRH also up-regulates IL-18 expression by increasing intracellular reactive oxygen in microglia cells. Here we report the relationship between CRH, microglia and mental disorders.
Autoimmunity is a disease that occurs when the body tissue is attacked by its own immune system. ... more Autoimmunity is a disease that occurs when the body tissue is attacked by its own immune system. Multiple sclerosis (MS) is an autoimmune illness which triggers neurological progressive and persistent functions. MS is associated with an abnormal B-cell response and upregulation of T-cell reactivity against a multitude of antigens. Mast cells are the first line of the innate immune system and act by de-granulating and secreting chemical mediators and cytokines. Their participation on the central nervous system has been recognized since the beginning of the last century. They have an important role in autoimmune disease, including MS where they mediate inflammation and demyelinization by presenting myelin antigens to T cells or disrupting the blood–brain barrier and permitting entry of inflammatory cells and cytokines. The participation of mast cells in MS is demonstrated by gene overexpression of chemical mediators and inflammatory cytokines. Here we report the relationship and involvement between mast cells and multiple sclerosis.
Atherosclerosis is an inflammatory disease and hyperlipidaemia is one of the main risk factors fo... more Atherosclerosis is an inflammatory disease and hyperlipidaemia is one of the main risk factors for aging, hypertension and diabetes. Variance in plasma LDL cholesterol concentration may be associated with differences in cardiovascular disease risk and high levels of lipids are associated with increased risk of developing atherosclerosis. Macrophages, which generate pro-inflammatory cytokines, mainly interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-alpha), are deeply involved in atherosclerosis, as well as mast cells which generate several cytokines, including IL-6 and IFN-gamma, and chemokines such as eotaxin, MCP-1 and RANTES involved in monocyte recruitment and differentiation in the arterial wall. In addition, mast cells participate in lipid retention and vascular cell remodeling, and are mediators of innate and adaptive immunity during atherosclerosis. Mast cells which accumulate in the human arterial intima and adventitia during atherosclerotic plaque progression, release vasoactive and angiogenic compounds, and pro-inflammatory mediators, such as arachidonic acid metabolites, histamine, cytokines/chemokines, platelet activating factor (PAF) and proteolytic enzymes. Mast cells can be activated by pro-inflammatory stimuli, including cytokines, hypercholesterolemia, and hyperglycemia, and trigger the endothelial expression of adhesion molecules such as P-selectin, vascular cell adhesion molecule-1 (VCAM-1) and chemokines which mediate the recruitment and adhesion of leukocytes. The participation of mast cells in atherosclerosis is still an enigma and it may be of therapeutic interest to clarify this process.
Mast cells (MCs) derive from a distinct precursor in the bone marrow and are predominantly found ... more Mast cells (MCs) derive from a distinct precursor in the bone marrow and are predominantly found in tissues at the interface between the host and the external environment where they can secrete mediators without overt degranulation. Mast cells mature under local tissue microenvironmental factors and are
necessary for the development of allergic reactions, through crosslinking of their surface receptors for IgE (FcεRI), leading to degranulation and the release of vasoactive, pro-inflammatory and nociceptive mediators that include histamine, pro-inflammatory and anti-inflammatory cytokines and proteolytic
enzymes. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demylination within the central nervous system. MCs are involved in the pathogenesis of MS by generating various vasoactive mediators and cytokines and participate in the destruction of the myelin sheath and the
neuronal cells. The process of the development of demyelinating plaques in MS is probably linked with the rupture of the blood–brain barrier by MC products. The effects of natalizumab, which is a very effective drug in reducing the annualized relapse rate and other relapse-based endpoints, are discussed. Here, we report the relationship between MCs and MS.
Neuropeptides are involved in neurogenic inflammation where there is vasodilation and plasma prot... more Neuropeptides are involved in neurogenic inflammation where there is vasodilation and plasma protein
extravasion in response to this stimulus. Nerve growth factor (NGF), identified by Rita Levi Montalcini,
is a neurotrophin family compound which is important for survival of nociceptive neurons during
their development. Therefore, NGF is an important neuropeptide which mediates the development
and functions of the central and peripheral nervous system. It also exerts its proinflammatory action,
not only on mast cells but also in B and T cells, neutrophils and eosinophils. Human mast cells can be
activated by neuropeptides to release potent mediators of inflammation, and they are found throughout
the body, especially near blood vessels, epithelial tissue and nerves. Mast cells generate and release NGF
after degranulation and they are involved in iperalgesia, neuroimmune interactions and tissue inflammation.
NGF is also a potent degranulation factor for mast cells in vitro and in vivo, promoting differentiation
and maturation of these cells and their precursor, acting as a co-factor with interleukin-3. In conclusion,
these studies are focused on cross-talk between neuropeptide NGF and inflammatory mast cells.
Inflammation, neurodegeneration, imbalance of neurotransmitter systems, oxidative stress and depr... more Inflammation, neurodegeneration, imbalance of neurotransmitter systems, oxidative stress and depression are all risk factors for obesity. There is evidence regarding the cross-talk between adipose tissue and the immune system and obese patients may show an alteration of immune functions with major depression, including immune suppression with reduced T-cell and macrophage activity. Obesity is mediated by inflammatory cells such as lymphocytes, macrophages and mast cells which release pro-inflammatory cytokines and chemokines. Obesity-induced leukocyte infiltrations in adipose tissue cause cytokine/chemokine release and inflammation. Here, we report the relationship between obesity, neurological alterations and inflammation.
Asthma is a chronic inflammatory disease of the lung and its pathophysiology is initiated by mast... more Asthma is a chronic inflammatory disease of the lung and its pathophysiology is initiated by mast cell activation in response to the antigen binding to IgE receptor as well as by TH2 cell activation. Mast cells are well established effector cells in asthma where they exacerbate the inflammatory response, playing a key role in early phase, degranulating and increasing histamine. Human mast cells possess high affinity IgE receptors and are ubiquitous but predominantly localized in mucosal and connective tissue and are distributed along blood vessels. There are two types of mast cells: connective tissue mast cells (TC) and mucosal mast cells (T mast cells). TC mast cells contain more heparin, whereas T mast cells contain more chondroitin sulfate. In asthma, mast cell activation can trigger degranulation, releasing secretory granule complex and preformed mediators, such as histamine and proteases, along with the synthesis of leukotrines and prostaglandins, and induction of cytokines and chemokines. Leukotrine inhibitors and omalizumab, which inhibits IgE, both relieve the asthma exacerbation when administered to humans and permit to reduce the use of other drugs. The release of cytokines by mast cells, such as TNF-alpha, IL-1, IL-6 and IL-33, participate in the pathogenesis of asthma. Stress worsens asthma, and this effect
is also mediated by mast cell activation through the release of cytokines. Administration of IL-33 in experimental animals provokes pathological effects in the mucosal tissues and augments antibody IgE and IgA in blood vessels. Here, we report the impact of mast cell biology in asthma pathogenesis.
Mast cells (MCs) are mediators of allergy and inflammation and participate in the growth of cance... more Mast cells (MCs) are mediators of allergy and inflammation and participate in the growth of cancer
cells. MCs can promote both neoangiogenesis and tumor growth. They increase in the stroma of certain
tumors where they can be recruited by tumor-derived chemoattractants, such as monocyte chemotactic
protein-1 (MCP-1), RANTES and stem cell factor (SCF) to selectively secrete inflammatory molecules
including chemical mediators and cytokines (TNF, IL-6 and IL-1). However, MC differentiation pathways
and heterogeneity in cancer are still poorly understood. Human interleukin 1 (IL-1) plays a pivotal role
in the pathogenesis of many diseases and functions, including host response to microbial invasion, injury
inflammatory processes, immunologic challenges and cancer. Inflammation around the tumor includes
the infiltration of mast cells and facilitates cancer growth. MCs are activated by IL-1 which can be
produced by certain cancer cells and stimulate the stromal cells to selectively release IL-6, contributing
to the development of Th-17 cells and increasing inflammation. IL-37, mainly generated by macrophage
cell line, is an IL-1 family member which binds IL-18 receptor α (IL-18Rα) chain, and acts as a natural
inhibitor of immune responses. IL-37 down-regulates cJun induced by IL-1, pro-inflammatory signals
and reduces the expression of the mitogen-activated protein kinase (MAPK) p38α, STAT transcription
factors and p53, affecting cellular differentiation and proliferation. In the present study we report the
relationship between inflammatory mast cells, cancer and the beneficial effect of IL-37.
Journal of biological regulators and homeostatic agents
Multidrug resistance (MDR) to anticancer chemotherapy is often mediated by the overexpression of ... more Multidrug resistance (MDR) to anticancer chemotherapy is often mediated by the overexpression of the plasma membrane drug transporter P-glycoprotein (Pgp) encoded by multidrug resistance gene (MDR1). Various chemosensitizing agents are able to inhibit Pgp activity but their clinical application is limited by their toxicity. Furthermore, hepatotoxicity related to chemotherapy causes delays of treatment in cancer patients and often requires supplementation of anti-tumour therapy with hepatoprotective agents. In this in vitro study, we investigated the effectiveness of an endogenous hepatoprotective agent, S-adenosylmethionine (SAMe), and a natural hepatoprotective compound, Cynarin (Cyn), to inhibit Pgp activity in order to evaluate their potential use as chemosensitizing agents. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) expressing high levels of Pgp were treated with two hepatoprotectors at various concentrations (1, 5 and 10 microM) that are clinically ac...
Cytokines are involved in the regulation of the immune system and clearly communicate with immune... more Cytokines are involved in the regulation of the immune system and clearly communicate with immune cells and bone cells. Therefore, cytokines are produced by many different cell types and are state. Cytokines such as IL-1, TNF, IL-6, TGF-b, IL-2, IL-8, M-CSF, IL-12, IL-18 and IFN-, and anti-resorption. The immune system and bone cells require positive and negative regulators to maintain homeostasis. In this article, we discuss the interactions between cytokines and bone cells in maintaining homeostasis of the bone. However, the relationship between intercellular signalling, osteoprogenitor cells, mature osteoblasts, osteocytes and osteoclasts, in regulating the pathophysiology of the bone, still remains to be elucidated. Editorial.
Endocrinology systems exert an important effect on vascular function and have direct actions on b... more Endocrinology systems exert an important effect on vascular function and have direct actions on blood vessels. Estrogens provoke an increase in skin elasticity, epidermal hydration, skin thickness, reduce skin wrinkles and augment the content of collagen and the level of vascularisation. Therefore, there is an intricate cross-talk between skin conditions and stress. In stress, β2-adrenoreceptor (β2AR) pathway, cortisol, epinephrine and norepinephrine increase DNA damage and interfere with the regulation of the cell cycle, contributing to aging and skin diseases. Substance P is a neuropeptide released in the skin from the peripheral nerve and is related to stress and inflammation. SP provokes infiltration of inflammatory cells in the skin and induces a variety of cytokines/chemokines. Corticotropin-releasing hormone (CRH), produced by mast cells, is a neuropeptide also expressed in skin and responds to stress. CRH initiates diverse intracellular signaling pathways, including cAMP, protein kinase C, and mitogen-activated protein kinases (MAPK). Under stress, CRH, glucocorticoids, epinephrine and cytokines are generated. Moreover, the release of ACTH binds the receptor MC2-R and stimulates the generation of glucocorticoids such as corticosterone and cortisol, which interact with the transcription factors AP-1 and NF-kB. In skin keratinocytes, ACTH promotes the generation of pro-inflammatory cytokines, which enhances T-cell activity. Cortisol is immunosuppressive by inhibiting Th1 and Th2 cell response, antigen presentation, antibody and cytokine/chemokine production. However, glucocorticoids are certainly helpful in Th1-mediated autoimmune disorders. On the other hand, cytokines, such as TNF, IL-1 and IL-6, stimulate the generation of CRH and activate HPA axis in inflammatory states. Here, we describe for the first time a cross-talk between endocrinology and skin, including pro-inflammatory cytokines and neurogenic inflammatory pathways.
Translational Research, 2009
Chemokines are cytokines with chemotactic properties on inflammatory cells and other cell types. ... more Chemokines are cytokines with chemotactic properties on inflammatory cells and other cell types. Chemokine (C-C motif) ligand 2 (CCL2), which is also called monocyte chemotactic protein 1 (MCP-1), is a potent chemotactic molecule that attracts lymphocytes, monocytes, mast cells, and memory T cells, but not neutrophils. CCL2/MCP-1 represents a link between the activation of monocytes, lymphocytes, basophils, mast cells, and eosinophils in inflammatory disorders, such as the late-phase allergic reaction. This C-C chemokine also plays a role in regulating Th-cell cytokine production and leukocyte trafficking. Laboratory of allergic diseases (LAD) cells is the first reported human mast cell line that closely resembles a primary culture of CD34+-derived human mast cells. These cells were cultured in vitro and treated with different concentrations of substance P (SP) for the production of CCL2/MCP-1. We used calcium ionophore as a positive control for stimulating transcription and translation of CCL2/MCP-1. The stimulation of SP on CCL2/MCP-1 was statistically significant (P < 0.05) compared with the control (untreated cells). In this study, we determined the expression and secretion of CCL2/MCP-1 from SP-activated LAD2 human mast cells in vitro. The levels of CCL2/MCP-1 from SP-activated LAD2 human mast cells were higher at 10 microM and at 18 h incubation compared with controls. This effect was also revealed on CCL2/MCP-1 messenger RNA (mRNA) expression, as determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Our data suggest that SP is an important neurotransmitter that can stimulate the chemokine CCL2, which plays a fundamental role in inflammation by recruiting inflammatory cells to specific cites.
Neurotoxicity Research, 2007
Lateral Sclerosis (ALS), Parkinsooism Dementia Complex, etc., and it causes extensive damage to t... more Lateral Sclerosis (ALS), Parkinsooism Dementia Complex, etc., and it causes extensive damage to the nervous system, including the impairment of learning and memory. However, to date, the mechanism of Al neurotoxicity has not been fully elucidated. Neuronal apoptosis has become a focus of interest, as it has been reported to play a key role in the impairment of learning and memory processes (Thompson, Science 267:1456, 1995). The Bcl-2 gene acts as an important effector for inhibiting apoptosis. In the present study we observe neuronal apoptosis in association with learning and memory impairment, as well as regional brain alterations in BcI-2 expression in rats chronically exposed to Al. The chronic Al-intoxicated model was established by i.p. injection of AICI3 in adult Sprague Dawley rats for 3 successive days, with one-day intervals, for 60 days. After exposure, the step-down test was performed to examine the behavioral reaction of the rats. Neuronal apoptosis and Bcl-2 protein expression in different regions of rat brain were then assessed by an immunohistochemical method. In the step-down test, the latency of Al-exposed rats was significantly lower than that of controls. Also, the num-ber of performance errors in 5 minutes of exposure was significantly higher than that of controls. Neuronal apoptosis was extensive in the brain of Al-exposed groups, and the expressions of Bcl-2 protein in frontal cortex, cerebellum and hippocampus of Al-exposed rats was stronger. In conclusion, chronic Al-exposure in rats is associated with neuronal apoptosis in brain, and impaired learning and memory. Augmented Bcl-2 protein expression may be a stimulated compensatory mechanism.
International Archives of Occupational and Environmental Health, 1999
The objective of this study was to analyze the role of some trace metals in the immune system of ... more The objective of this study was to analyze the role of some trace metals in the immune system of nonallergic or atopic men. One of these elements (Zn) is essential for immune function, whereas others, present in the urban environment, are known to be allergenic (Ni and Cr) or toxic (Pb). Serum levels of interleukin (IL) 2, 4, 5, and 13 and of interferon-y and immunoglobulins, blood lymphocyte subsets, blood concentrations of Pb and Zn, serum levels of Zn, and urinary Cr and Ni concentrations were determined in 17 nonallergic men (mean age 34 years) and 17 healthy nonsymptomatic atopic men living in urban areas. The mean blood concentration of Pb (a marker of exposure to toxic agents) was 11 microg/dl in both groups, which showed similar levels of blood Zn and of urinary Ni and Cr, whereas the serum Zn concentration was lower in the atopic group. Serum IgE levels were much higher in atopic men than in nonallergics, whereas serum IL-2, IL-5, and IL-13 concentrations were lower, possibly due to binding to tissue receptors and cells. Moreover, in atopic subjects, numbers of blood CD4+-CD45RO-"virgin" lymphocytes were significantly lower and the CD4+ -CD45RO+/CD4+ -CD45RO- ratio was more elevated, indicating an activation of the immune system. Serum IgE levels of atopic men, in contrast to those of nonallergic subjects, were correlated with CD19+ and CD5--CD19+ B lymphocytes. Blood Pb levels of both groups of men were correlated with CD4+, CD4+-CD45RO+, and HLA-DR+ [activated T-, B-, CO4+ -C. and natural killer (NK) cells] lymphocytes; in particular, blood Pb levels of the nonallergic men were also significantly correlated with CD25+ cells activated by IL-2, whereas those of the atopic men were also correlated with CD3--HLA-DR+ (B- and NK-cells) and CD5--CD19+ lymphocytes. Besides serum Zn levels, urinary Ni and Cr of nonallergic men were correlated with several immune parameters; in particular, urinary Cr was correlated with serum IL-5 and IgE and urinary Ni was correlated with CD4+ -CD45RO+ and CD3+ -CD25+ lymphocytes. This correlation of Ni and Cr, also found in previous studies in nonallergic subjects, confirms the hypothesis that these metals are involved in mechanisms of immune response regulation and that allergy to Ni or Cr represents an alteration of physiological mechanisms. Previous experimental studies have demonstrated that Pb exerts immunomodulatory effects on CD4+ and B- lymphocytes, enhancing the production of Th2-like cytokines and IgE. These experimental results confirm those of this study, showing in atopic men the correlation of B-lymphocytes with both blood Pb and serum IgE levels. This suggests that Pb may enhance the incidence of atopy in populations exposed to an urban environment.
Annals of clinical and laboratory science, 2003
Resveratrol, synthesized in dietary plants and contained in wine, has been reported to play a ben... more Resveratrol, synthesized in dietary plants and contained in wine, has been reported to play a beneficial role in certain cardiovascular regulatory mechanisms and to inhibit carcinogenesis by activating immune and inflammatory responses and apoptosis. The object of this study was to elucidate the "in vitro" effects of different concentrations of resveratrol (10(-4), 10(-5), and 10(-7) M) on human peripheral blood mononuclear cell (PBMC) proliferation and cytokine release. Spontaneous PBMC proliferation was unaffected by resveratrol, while the compound at 10(-4) M inhibited (69%) the PHA-stimulated PBMC proliferation. The proliferation stimulation index (ie, the ratio of PHA-stimulated PBMC proliferation/spontaneous PBMC proliferation) of cultures containing 10(-4) M resveratrol was very low in relation to the control, while the proliferation stimulation index values at 10(-5) and 10(-7) M were similar and slightly higher (without statistical significance), respectively. At ...
Neurotoxicity Research, 2009
Substance P (SP) is an important neuropeptide involved in neurogenic inflammation and most of its... more Substance P (SP) is an important neuropeptide involved in neurogenic inflammation and most of its pathophysiological functions are mediated through binding to the neurokinin-1 receptor. SP exerts various proinflammatory actions on immune-cells, including macrophages. Several compounds such as cytokines have the capacity to activate and stimulate macrophages to produce arachidonic acid oxygenation and lipoxygenation products. Leukotriene B4 (LTB4) is one of the most important mediators of leukocyte activation in acute and chronic inflammatory reactions. LTB4 stimulates chemotaxis, lysosomal enzyme release, and cell aggregation. In this report, we studied the effect of SP on rat adherent granuloma macrophages (RAGMs). The chronic granuloma in rat was induced by dorsal injections of a potassium permanganate (KMnO4) saturated crystal solution (200 microl of a 1:40 dilution). After 7 days, all rats developed a subcutaneous granuloma in the injection site from which infiltrated macrophages were extracted, isolated, and cultured in vitro. We tested the hypothesis that SP stimulates the production of LTB4 in RAGMs and increases lipoxygenase expression. Here we show that the cell-free supernatant of RAGMs stimulated with SP (10 microM), resulted in statistically significant increases of LTB4 Preincubation of RAGMs with NDGA (nordihydroguaiaretic acid (10 microM), completely abolished the production of LTB(4) in the supernatants and lipoxygenase expression on RAGMs challenged with SP, or the cation ionophore A23187 (positive control). Similar effects were obtained when the cells were pretreated with dexamethasone (10 microM). Our results suggest that SP is able to stimulate the release of LTB4 and lipoxygenase expression in macrophages from chronic inflammatory granuloma and provide further evidence for a neuroinflammatory pathway.
Cancer Immunology Immunotherapy, 1994
During the past decade, particular attention has been focused on treatment of bladder cancer pati... more During the past decade, particular attention has been focused on treatment of bladder cancer patients with the bacterial agent bacillus Calmette-Gu&in (BCG). In these studies, bladder cancer patients were instilled with BCG (75 rag/50 ml) once per week for 6 weeks, 1-2 weeks following trans-urethreal resection of the bladder. Cystoscopy was performed after 6 weeks and, unless tumor progression was present, monthly treatments were given for 1 year. Blood was drawn 2 h after the last instillation, and monocytes were isolated (5x 106 cells/ml) and treated, or not, with lipopolysaccharide (LPS) (20 gg/ml) for tumor necrosis factor a (TNFo~), interleukin-lo~ (IL-la) and interleukin-6 (IL-6) release. The levels of monokines were determined by a monokine-specific enzyme-linked immunosorbent assay. Our results clearly show that, after 18 h incubation, macrophages from BCG-treated bladder cancer patients produced from 2.8-to 1.9-fold and from 2.0-to 1.3-fold greater amounts of TNFo~ and IL-lc~ respectively, compared to macrophages from healthy controls, 5-fold higher than bladder cancer patients not treated with BCG. IL-6 was not affected. In another set of experiments macrophages (5x106 cells/ml) from healthy subjects were pretreated, or not, with BCG (100 gg/ml) overnight and treated, or not, with LPS 20 gg/ml alone and in combination with interleukin-1 receptor antagonist (IL-lra) 250 ng/ml. Macrophages treated with BCG had a strong stimulatory effect on IL-1 oc release (9.45 ng/ml) while LPS was less effective (3.59 ng/ml). The combination of BCG plus LPS produced an additive effect on IL-lo~ release (13.71 ng/ml) compared to the effect of the compound alone. The addition of IL-lra (250 ng/ml) to BCG was not effective, while when IL-lra was added to BCG plus LPS only a partial inhibition of IL-I~ release was found (9.83 ng/ml), compared to BCG plus LPS without IL-lra (13.71 ng/ml). These effects seem to be related to the inhibition of IL-lc~ stimulated with LPS, but not BCG. The priming effect of BCG exerted on LPS-stimulated monocyte production of TNFc~ and IL-1 o~ from bladder cancer patients led us to study the possible modulation of fibrinogen and C-reactive protein in the serum of BCGtreated cancer patients. The plasma levels of fibrinogen and C-reactive protein were higher (approximately twice) in BCG-treated patients compared to values obtained in untreated patients or healthy controls. We conclude that the beneficial immunotherapeutic effects of BCG in bladder cancer patients are related to its capacity to prime macrophages to enhance the release of TNFc~ and IL-I~, but not IL-6 in response to physiological secondary stimuli, or through the direct stimulation of BCG on IL-la or TNFo~ which are directly involved in the killing of cancer cells. Moreover, the increase of IL-lc~ or TNFc~ in BCG bladder cancer patients may lead to high plasma levels of fibrinogen and C-reactive protein, two proteins responsible for the acute-phase response.
Vitamin E is found in eight forms in nature which include four tocopherols (alpha, beta, gamma an... more Vitamin E is found in eight forms in nature which include four tocopherols (alpha, beta, gamma
and delta) and four tocotrianols (alpha, beta, gamma and delta). The classic effect of vitamin E is to
reduce and prevent oxygen damage to the tissue and is useful for the treatment of pain, inflammation
and allergic reactions. In addition to antioxidant activity, vitamin E also has a number of different and
related functions. It protects against cancer, improves immune response, lowers the incidence of infectious
diseases, cardiovascular diseases and is protective in allergy and asthma risk, and other disorders. Vitamin E increases n-6 polyunsaturated fatty acid (PUFA) and decreases n-3 PUFA, an effect that diminishes asthma and allergic diseases. Moreover, vitamin E regulates vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration through its oxidant and non-antioxidant effect. Furthermore, vitamin E modulates the endothelial function by altering VCAM-1-induced oxidative activation of endothelial cell PKCα. However, vitamin E is not consistently associated with asthma and/or allergy, and in some cases there are conflicting results on allergy and inflammatory diseases. The association of vitamin E and allergy appears to be very complex, and further study needs to clarify this dilemma.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2007
To investigate the association between plasma interleukin-18 (IL-18) levels and atherosclerosis i... more To investigate the association between plasma interleukin-18 (IL-18) levels and atherosclerosis in patients with obstructive obstructive sleep apnea hypopnea syndrome (OSAHS). Based on apnea hypopnea index (AHI) during sleep monitored by polysomnography, 52 male patients with OSAHS were recruited and divided into a mild OSAHS group (n = 16), a moderate group (n = 18), and a severe group (n = 18). Eighteen healthy subjects were selected as the control group. Twenty patients with moderate-to-severe OSAHS underwent continuous positive airway pressure (CPAP) treatment. HDL5000 color Doppler ultrasound was used to measure intima-media thickness (IMT) of the jugular arteries. Plasma IL-18 levels were measured by ELISA. Analysis of variance, paired-samples T test and Pearson correlation analysis were used for statistics. Compared with the plasma IL-18 levels in the control group [(250 +/- 76) ng/L], there was a significant increase in the mild OSAHS group [(352 +/- 76) ng/L], moderate grou...
Inflammation Research, 1990
Microglia derive from mononuclear myeloid progenitors and are a major glial complement of product... more Microglia derive from mononuclear myeloid progenitors and are a major glial complement of products are implicated in the neuronal destruction usually observed in various neurodegenerative diseases. Microglia cells express corticotropin releasing hormone (CRH) receptors, and activation of microglia by CRH releases bioactive molecules which have a biological effect in the brain and regulate several neurological diseases. CRH plays a pivotal role in stress responses and is a key mediator of the hypothalamic-pituitary-adrenocortical system. CRH is expressed in human mast cells, leading to and act synergistically to increase vascular permeability. CRH also up-regulates IL-18 expression by increasing intracellular reactive oxygen in microglia cells. Here we report the relationship between CRH, microglia and mental disorders.
Autoimmunity is a disease that occurs when the body tissue is attacked by its own immune system. ... more Autoimmunity is a disease that occurs when the body tissue is attacked by its own immune system. Multiple sclerosis (MS) is an autoimmune illness which triggers neurological progressive and persistent functions. MS is associated with an abnormal B-cell response and upregulation of T-cell reactivity against a multitude of antigens. Mast cells are the first line of the innate immune system and act by de-granulating and secreting chemical mediators and cytokines. Their participation on the central nervous system has been recognized since the beginning of the last century. They have an important role in autoimmune disease, including MS where they mediate inflammation and demyelinization by presenting myelin antigens to T cells or disrupting the blood–brain barrier and permitting entry of inflammatory cells and cytokines. The participation of mast cells in MS is demonstrated by gene overexpression of chemical mediators and inflammatory cytokines. Here we report the relationship and involvement between mast cells and multiple sclerosis.
Atherosclerosis is an inflammatory disease and hyperlipidaemia is one of the main risk factors fo... more Atherosclerosis is an inflammatory disease and hyperlipidaemia is one of the main risk factors for aging, hypertension and diabetes. Variance in plasma LDL cholesterol concentration may be associated with differences in cardiovascular disease risk and high levels of lipids are associated with increased risk of developing atherosclerosis. Macrophages, which generate pro-inflammatory cytokines, mainly interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-alpha), are deeply involved in atherosclerosis, as well as mast cells which generate several cytokines, including IL-6 and IFN-gamma, and chemokines such as eotaxin, MCP-1 and RANTES involved in monocyte recruitment and differentiation in the arterial wall. In addition, mast cells participate in lipid retention and vascular cell remodeling, and are mediators of innate and adaptive immunity during atherosclerosis. Mast cells which accumulate in the human arterial intima and adventitia during atherosclerotic plaque progression, release vasoactive and angiogenic compounds, and pro-inflammatory mediators, such as arachidonic acid metabolites, histamine, cytokines/chemokines, platelet activating factor (PAF) and proteolytic enzymes. Mast cells can be activated by pro-inflammatory stimuli, including cytokines, hypercholesterolemia, and hyperglycemia, and trigger the endothelial expression of adhesion molecules such as P-selectin, vascular cell adhesion molecule-1 (VCAM-1) and chemokines which mediate the recruitment and adhesion of leukocytes. The participation of mast cells in atherosclerosis is still an enigma and it may be of therapeutic interest to clarify this process.
Mast cells (MCs) derive from a distinct precursor in the bone marrow and are predominantly found ... more Mast cells (MCs) derive from a distinct precursor in the bone marrow and are predominantly found in tissues at the interface between the host and the external environment where they can secrete mediators without overt degranulation. Mast cells mature under local tissue microenvironmental factors and are
necessary for the development of allergic reactions, through crosslinking of their surface receptors for IgE (FcεRI), leading to degranulation and the release of vasoactive, pro-inflammatory and nociceptive mediators that include histamine, pro-inflammatory and anti-inflammatory cytokines and proteolytic
enzymes. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demylination within the central nervous system. MCs are involved in the pathogenesis of MS by generating various vasoactive mediators and cytokines and participate in the destruction of the myelin sheath and the
neuronal cells. The process of the development of demyelinating plaques in MS is probably linked with the rupture of the blood–brain barrier by MC products. The effects of natalizumab, which is a very effective drug in reducing the annualized relapse rate and other relapse-based endpoints, are discussed. Here, we report the relationship between MCs and MS.
Neuropeptides are involved in neurogenic inflammation where there is vasodilation and plasma prot... more Neuropeptides are involved in neurogenic inflammation where there is vasodilation and plasma protein
extravasion in response to this stimulus. Nerve growth factor (NGF), identified by Rita Levi Montalcini,
is a neurotrophin family compound which is important for survival of nociceptive neurons during
their development. Therefore, NGF is an important neuropeptide which mediates the development
and functions of the central and peripheral nervous system. It also exerts its proinflammatory action,
not only on mast cells but also in B and T cells, neutrophils and eosinophils. Human mast cells can be
activated by neuropeptides to release potent mediators of inflammation, and they are found throughout
the body, especially near blood vessels, epithelial tissue and nerves. Mast cells generate and release NGF
after degranulation and they are involved in iperalgesia, neuroimmune interactions and tissue inflammation.
NGF is also a potent degranulation factor for mast cells in vitro and in vivo, promoting differentiation
and maturation of these cells and their precursor, acting as a co-factor with interleukin-3. In conclusion,
these studies are focused on cross-talk between neuropeptide NGF and inflammatory mast cells.
Inflammation, neurodegeneration, imbalance of neurotransmitter systems, oxidative stress and depr... more Inflammation, neurodegeneration, imbalance of neurotransmitter systems, oxidative stress and depression are all risk factors for obesity. There is evidence regarding the cross-talk between adipose tissue and the immune system and obese patients may show an alteration of immune functions with major depression, including immune suppression with reduced T-cell and macrophage activity. Obesity is mediated by inflammatory cells such as lymphocytes, macrophages and mast cells which release pro-inflammatory cytokines and chemokines. Obesity-induced leukocyte infiltrations in adipose tissue cause cytokine/chemokine release and inflammation. Here, we report the relationship between obesity, neurological alterations and inflammation.
Asthma is a chronic inflammatory disease of the lung and its pathophysiology is initiated by mast... more Asthma is a chronic inflammatory disease of the lung and its pathophysiology is initiated by mast cell activation in response to the antigen binding to IgE receptor as well as by TH2 cell activation. Mast cells are well established effector cells in asthma where they exacerbate the inflammatory response, playing a key role in early phase, degranulating and increasing histamine. Human mast cells possess high affinity IgE receptors and are ubiquitous but predominantly localized in mucosal and connective tissue and are distributed along blood vessels. There are two types of mast cells: connective tissue mast cells (TC) and mucosal mast cells (T mast cells). TC mast cells contain more heparin, whereas T mast cells contain more chondroitin sulfate. In asthma, mast cell activation can trigger degranulation, releasing secretory granule complex and preformed mediators, such as histamine and proteases, along with the synthesis of leukotrines and prostaglandins, and induction of cytokines and chemokines. Leukotrine inhibitors and omalizumab, which inhibits IgE, both relieve the asthma exacerbation when administered to humans and permit to reduce the use of other drugs. The release of cytokines by mast cells, such as TNF-alpha, IL-1, IL-6 and IL-33, participate in the pathogenesis of asthma. Stress worsens asthma, and this effect
is also mediated by mast cell activation through the release of cytokines. Administration of IL-33 in experimental animals provokes pathological effects in the mucosal tissues and augments antibody IgE and IgA in blood vessels. Here, we report the impact of mast cell biology in asthma pathogenesis.