Important role of mast cells in multiple sclerosis.

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 degranulating 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.

Neuroinflammation Induces Neurodegeneration.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple Sclerosis (MS) are characterized by neuronal degeneration and neuronal death in specific regions of the central nervous system (CNS). In AD, neurons of the hippocampus and entorhinal cortex are the first to degenerate, whereas in PD, dopaminergic neurons in the substantia nigra degenerate. MS patients show destruction of the myelin sheath. Once the CNS neurons are damaged, they are unable to regenerate unlike any other tissue in the body. Neurodegeneration is mediated by inflammatory and neurotoxic mediators such as interleukin-1beta (IL-1ß), IL-6, IL-8, IL-33, tumor necrosis factor-alpha (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), CCL5, matrix metalloproteinase (MMPs), granulocyte macrophage colony-stimulating factor (GM-CSF), glia maturation factor (GMF), substance P, reactive oxygen species (ROS), reactive nitrogen species (RNS), mast cells-mediated histamine and proteases, protease activated receptor-2 (PAR-2), CD40, CD40L, CD88, intracellular Ca+ elevation, and activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-B (NF-kB). Activated microglia, astrocytes, neurons, T-cells and mast cells release these inflammatory mediators and mediate neuroinflammation and neurodegeneration in a vicious manner. Further, immune and inflammatory cells and inflammatory mediators from the periphery cross the defective blood-brain-barrier (BBB) and augment neuroinflammation. Though inflammation is crucial in the onset and the progression of neurodegenerative diseases, anti-inflammatory drugs do not provide significant therapeutic effects in these patients till date, as the disease pathogenesis is not yet clearly understood. In this review, we discuss the possible factors involved in neuroinflammation-mediated neurodegeneration.

Interrelationship between vitamins and cytokines in immunity.

Cytokines are important proteins that modulate immunity and inflammation. Vitamins are also involved in immunity and inflammation. They are found to restore the ability of some cells to produce certain cytokines. Vitamin deficiency appears to affect the mechanism of immune cells, though the impact of reduced cytokine response in vitamin malnutrition is not clear. Vitamin D is involved in many medical conditions, such as infections and inflammation, and mediates innate immunity. Deficiency of vitamin D increases the risk of infectious and inflammatory diseases. In addition, this vitamin modulates Treg function and IL-10 production which is important for therapeutic treatment. Vitamin A increases inflammatory response and is involved in tissue damage; moreover, vitamin A is a key modulator of TGFbeta which can suppress several cytokines. Vitamin E, an anti-ageing compound, is associated with a defect of naive T cells and may inhibit some inflammatory compounds such as prostaglandin generation.

IL-35, an anti-inflammatory cytokine which expands CD4+CD25+ Treg Cells.

Interleukin 12 (IL 12) p35/p40 is a heterodimeric cytokine which plays a critical role in inflammation, immunity and tissue proliferation, and also plays a relevant function in T helper (Th) cell polarization and Th1 T-cell differentiation. IL-12 family members, IL-12p70, IL-23, IL-27 and IL-35, play an important role in influencing helper T-cell differentiation. EBV-induced gene 3 can be associated with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, also called IL-35. It has been shown that IL-35 has biological activity and able to expand CD4+CD25+ Treg cells, suppress the proliferation of CD4+CD25- effector cells and inhibit Th17 cell polarization. IL-35 has been shown to be constitutively expressed by regulatory T (Treg) cells CD4(+)CD25(+)Foxp3(+) and suggested to contribute to their suppressive activity. IL-35 is a crucial mediator which provokes CD4+CD25+ T cell proliferation and IL-10 generation, another well-known anti-inflammatory cytokine, along with TGFbeta cytokine. These studies suggest that IL-35, together with other successfully discovered cytokine inhibitors, represents a new potential therapeutic cytokine for chronic inflammation, autoimmunity and other immunological disorders.

Impact of RANTES, MCP-1 and IL-8 in mast cells.

Chemokines are cytokines with chemotactic properties on inflammatory cells and other cell types. RANTES, MCP-1 and related molecules, constitute the C-C class of chemokine supergene family and a group of cytokines produced by hematopoietic cells, while IL-8 constitute the C-X-C class. The roles of most of these chemokines are not well known, although members of the chemokine family are inflammatory agents. The C-C chemokine plays a role in regulating Th-cell cytokine production and leukocyte trafficking. In this study we clearly show that RANTES and MCP-1 are mediators of acute inflammatory responses. Our report describes additional biological activities for RANTES, MCP-1, and IL-8, suggesting that these chemokines play a fundamental role in histamine and serotonin generation and cell function in mast cells.

Luteolin and thiosalicylate inhibit HgCl(2) and thimerosal-induced VEGF release from human mast cells.

HgCl2 is a known environemental neurotoxin, but is also used as preservative in vaccines as thimerosal containing ethyl mercury covalently linked to thiosalicylate. We recently reported that mercury choloride (HgCl(2)) can stimulate human mast cells to release vascular endothelial growth factor (VEGF), which is also vasoactive and pro-inflammatory. Here we show that thimerosal induces significant VEGF release from human leukemic cultured LAD2 mast cells (at 1 microM 326 ± 12 pg/106 cells and 335.5 ± 12 pg/106 cells at 10 microM) compared to control cells (242 ± 21 pg/106 cells, n=5, p less than 0.05); this effect is weaker than that induced by HgCl2 at 10 microM (448 ± 14 pg/106 cells) (n=3, p less than 0.05). In view of this finding, we hypothesize that the thiosalicylate component of thimerosal may have an inhibitory effect on VEGF release. Thimerosal (10 microM) added together with the peptide Substance P (SP) at 2 microM, used as a positive control, reduced VEGF release by 90 percent. Methyl thiosalicylate (1 or 10 microM) added with either SP or HgCl2 (10 microM) inhibited VEGF release by 100 percent, while sodium salicylate or ibuprofen had no effect. Pretreatment for 10 min with the flavonoid luteolin (0.1 mM) before HgCl2 or thimerosal compeletly blocked their effect. Luteolin and methyl thiosalicylate may be useful in preventing mercury-induced toxicity.

IL-32: a newly-discovered proinflammatory cytokine.

IL-32, a newly-discovered proinflammatory cytokine that activates the p38MAPK and NF-kappaB pathways, is an important player in innate and adaptive immune response. IL-32, a cytokine produced mainly by T, natural killer, and epithelial cells induces significant amounts of TNFalpha and MIP-2 and increases the production of both cytokines in a dose-dependent manner. IL-32 has been implicated in inflammatory disorders, mycobacterium tuberculosis infections, inflammatory bowel disease, and influenza A virus infection, as well as in some autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis and Crohn?s disease and in human stomach cancer, human lung cancer and breast cancer tissues. Moreover, it has been reported that IL-32 has pro-inflammatory effects on myeloid cells and causes the differentiation of osteoclast precursors into multinucleated cells expressing specific osteoclast markers. We recently found that human IL-32 has the capacity to provoke histamine release in human-derived cord blood mast cells (HDCBMC), but not in LAD 2 cells nor in rat peritoneal mast cells (RPMC), showing that IL-32 may be specie specific and act more in mature human mast cells (HDCBMC) than in transformed mast cells (LAD 2 cells). Certainly, IL-32 is another potent proinflammatory cytokine, however, the specific role of this newly-discovered protein in the network of cytokine biology remains to be determined.

Autism and immunity: revisited study.

Autism spectrum disorder is of interest neurochemically because it represents a relatively homogeneous disorder with regard to disease development, abnormal cognitive development and intellectual development disturbance. A consistent finding in autistic children is a high number of mast cells and a high level of serotonin which is also found at elevated concentrations in the urine of autistic patients. In addition, a dysfunction of clinical conditions, such as gastrointestinal and immunological symptoms, is frequently noted in autistic children, however, IgE does not appear to be prevalent in these children but probably an increase of cytokines/chemokines produced by mast cells at an early age may play an important role. Therefore an immune hypothesis, involving also autoimmunity, is one possible pathogenetic mechanism in autism. In conclusion, mast cell activation could contribute to immune and neuroinflammatory abnormalities that are evident in patients with autism spectrum disorders.

The latest interleukin: IL-33 the novel IL-1-family member is a potent mast cell activator.

IL-33, a member of IL-1 family, induces the differentiation of T-cells (depending on the phosphorylation of MAPKs and NF-kB) and is involved in T-cell mediated immune responses. IL-33 is also involved in the production of IL-5, IL-4 and IL-13 and several chemokines. In this editorial we show the importance of IL-33 in allergic diseases and its role as an inflammatory cytokine. In addition, the induction of certain chemokines by IL-33 may candidate this new cytokine as a mediator in inflammatory and autoimmune diseases and may prove to be a therapeutic target for the prevention of these diseases.

Urticaria pigmentosa associated with acute stress and lesional skin mast-cell expression of CRF-R1.

A 38-year-old woman presented with a pronounced increase in symptoms and proliferation of urticaria pigmentosa (UP) after acute psychological stress, which was quantified using the Spielberger's State-Trait Anxiety Inventory. Immunohistochemical examination of a skin biopsy from a new UP lesion showed a large number of activated mast cells expressing corticotrophin-releasing factor receptor-1 (CRF-R1) and there was high serum CRF. This is the first documented report to our knowledge of UP worsening associated with acute stress, possibly through activation of skin mast-cell CRF-R1.

Treatment of refractory interstitial cystitis/painful bladder syndrome with CystoProtek--an oral multi-agent natural supplement.

OBJECTIVES: Interstitial cystitis/Painful bladder syndrome (IC/PBS) is a chronic bladder condition of unknown etiology and pathogenesis. However, there is evidence of bladder surface mucosal and glycosaminoglycans (GAG) dysfunction in IC/PBS and GAG replacement therapy has been used to treat the condition. The results of an open label, uncontrolled study of a dietary supplement designed to improve GAG mucopolysaccharides integrity (glucosamine sulfate, sodium hyaluronate and chondroitin sulfate) and reduce bladder wall inflammation (quercetin, rutin) are presented herein. METHODS: Two hundred fifty two IC/PBS patients (25 men, 227 women; 18-69 years old), who had failed other treatments, took four CystoProtek capsules /day (mg/capsule: glucosamine sulfate, 120; chondroitin sulfate, 150; hyaluronate sodium, 10; quercetin, 150; rutin, 20). Symptoms were evaluated using a visual analogue scale (VAS) (severity range from 1-10) before and after treatment (< 6, 6-12 or > 12 months). The women were divided into two severity groups--a more severe A group with a baseline mean VAS score greater than or equal to 5 and a less severe B group with a mean score < 5. RESULTS: Male patients (55.72 +/- 9.53 years, n = 25) had a mean VAS score at baseline of 7.6 +/- 1.63 which fell 51.8% to 3.94 +/- 2.46 (p < 0.0001) after 12.46 +/- 8.76 months of treatment. The women (n = 227) experienced a 48.8% reduction in the mean VAS score (p < 0.0001) after 11.2 +/- 8.7 months. The mean VAS score in Group A (49.72 +/- 11.39 years, n = 207) fell 52.1% from 7.91 +/- 1.55 to 3.79 +/- 2.37 (p < 0.0001) after 11.06 +/- 8.18 months and in Group B (52.40 +/- 10.19 years, n = 20) fell 43.5% from 3.15 +/- 0.92 to 1.78 +/- 1.63 (p = 0.013) after 10.10 +/- 5.80 months. Patients in Group A and B were further subdivided into Groups A1, B1 (> 12 months), A2, B2 (6-12 months) and A3, B3 (< 6 months treatment); improvement was statistically significant in all the more severe Group A treatment duration subgroups. CONCLUSIONS: Dietary supplements targeting the bladder GAGs (chondroitin, glucosamine, hyaluronate) and bladder inflammation (quercetin, rutin) are useful in the treatment of refractory IC/PBS. Prospective randomized trials of such supplements are warranted in both treatment refractory and treatment naïve patients.

A quercetin containing supplement reduces niacin-induced flush in humans.

Coronary artery disease is associated with increased serum levels of cholesterol, triglycerides and LDL, but low levels of HDL. The most potent agent capable of reversing this trend is the vitamin nicotinic acid (niacin). However, compliance even with extended-release preparations and addition of acetylsalicylic acid (ASA) is hampered by the development of a feeling of erythema and burning ("flush"), especially on the face. We recently showed that the natural flavonoids quercetin and luteolin can eliminate "flush", as well as inhibit both niacin-induced plasma prostaglandin D2 (PGD2) and serotonin increase in an animal model. We conducted a pilot clinical study in humans. Four normal male subjects received (a) 1 g immediate release niacin either alone or after (b) the dietary formulation (Algonot-plus) containing 150 mg quercetin per capsule. Subjects completed a visual scale (1 = no, 5 = worst response) symptom assessment. Erythema and burning sensation scores were both 4.75+/-0.50 and lasted for 3.63+/-1.11 hours. After Algonot-plus administration, both scores were reduced to 2.5+/-0.58 and lasted only for 1.68+/-0.70 hours. Quercetin also inhibited methylnicotinate-induced human mast cell PGD2 release. These preliminary results suggest that quercetin could reduce niacin-induced "flush" in humans.

Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell-dependent stimulation of Jurkat T cells.

BACKGROUND AND PURPOSE: Allergic inflammation and autoimmune diseases, such as atopic dermatitis, psoriasis and multiple sclerosis (MS), involve both mast cell and T-cell activation. However, possible interactions between the two and the mechanism of such activations are largely unknown. EXPERIMENTAL APPROACH: Human umbilical cord blood-derived cultured mast cells (hCBMCs) and Jurkat T cells were incubated separately or together, following activation with myelin basic protein (MBP), as well as with or without pretreatment with the flavonoid luteolin for 15 min. The supernatant fluid was assayed for inflammatory mediators released from mast cells and interleukin (IL)-2 release from Jurkat cells. KEY RESULTS: MBP (10 microM) stimulates hCBMCs to release IL-6, IL-8, transforming growth factor (TGF)-beta1, tumour necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), histamine and tryptase (n=6, P<0.05). Addition of mast cells to Jurkat cells activated by anti-CD3/anti-CD28 increases IL-2 release by 30-fold (n=3, P<0.05). MBP-stimulated mast cells and their supernatant fluid further increase Jurkat cell IL-2 release (n=3, P<0.05). Separation of mast cells and activated Jurkat cells by a Transwell permeable membrane inhibits Jurkat cell stimulation by 60%. Pretreatment of Jurkat cells with a TNF-neutralizing antibody reduces IL-2 release by another 40%. Luteolin pretreatment inhibits mast cell activation (n=3-6, P<0.05), Jurkat cell activation and mast cell-dependent Jurkat cell stimulation (n=3, P<0.05). CONCLUSIONS AND IMPLICATIONS: Mast cells can stimulate activated Jurkat cells. This interaction is inhibited by luteolin, suggesting that this flavonoid may be useful in the treatment of autoimmune diseases.

Biology of neurotensin: revisited study.

The tridecapeptide neurotensin (NT) acts in the mammalian brain as a primary neurotransmitter or neuromodulator of classical neurotransmitters. Morphological and functional in vitro and in vivo studies have demonstrated the existence of close interactions between NT and dopamine both in limbic and in striatal brain regions. Additionally, biochemical and neurochemical evidence indicates that in these brain regions NT also plays a crucial role in the regulation of the aminoacidergic signalling. Immune cells, such as lymphocytes, macrophages and mast cells are reported to be activated by neuropeptides, such as neurotensin; this activation leads to cytokine and immunoglobulin production. In addition, neurotensin increases calcium level and the production of nitric oxide. Therefore neurotensin is deeply involved in immunity and inflammation but its real function still remains to be elucidated.

Intravesical nanocrystalline silver decreases experimental bladder inflammation.

PURPOSE: Interstitial cystitis is a sterile bladder inflammatory disease characterized by pelvic pain, urinary urgency and frequency. Nanocrystalline silver has anti-inflammatory properties, prompting us to investigate its effect in experimental bladder inflammation. MATERIALS AND METHODS: Nanocrystalline silver (0.01%, 0.05%, 0.1%, 0.5% or 1%) or phosphate buffered saline (Invitrogen) (0.5 ml) was introduced intravesically in Sprague-Dawley female rat (Charles River Laboratories, Wilmington, Massachusetts) bladders for 20 minutes, followed by vehicle or protamine sulfate (10 mg/ml for 30 minutes) and lipopolysaccharide (Sigma) (2 mg/ml for 45 minutes). Urine was collected throughout for histamine assay. The catheter was removed, the rat was returned to its cage and 4 hours later it was sacrificed. The bladder was harvested, minced and cultured overnight. The medium was collected for tumor necrosis factor-alpha assay. RESULTS: Mean +/- SD total urine histamine increased from 270 +/- 190 ng in 4 controls to 842 +/- 239 ng after protamine sulfate/lipopolysaccharide and it decreased to 505 +/- 187 ng in 6 animals after pretreatment with 1% nanocrystalline silver (p = 0.036). Tumor necrosis factor-alpha release in explant medium increased from 0.02 +/- 0.03 pg/mg in 6 controls to 0.28 +/- 0.15 pg/mg in 14 animals after treatment with protamine sulfate/lipopolysaccharide and it decreased to 0.12 +/- 0.11 pg/mg in 10 animals pretreated with nanocrystalline silver (p = 0.009). Nanocrystalline silver was not effective at less than 1% and at 1% alone it released 0.05 +/- 0.07 pg/mg tumor necrosis factor-alpha in 7 rats (vs phosphate buffered saline in 6, p = 0.387). Nanocrystalline silver (1%) significantly decreased bladder inflammation and mast cell activation. These effects were apparent even 4 days later. CONCLUSIONS: Intravesical administration of nanocrystalline silver (1%) decreased urine histamine, bladder tumor necrosis factor-alpha and mast cell activation without any toxic effect. This action may be useful for interstitial cystitis.

The flavonoid luteolin inhibits niacin-induced flush.

BACKGROUND AND PURPOSE: Sustained release niacin effectively lowers serum cholesterol, LDL and triglycerides, while raising HDL. However, 75% of patients experience cutaneous warmth and itching known as flush, leading to discontinuation. Acetylsalicylic acid (aspirin) reduces this flush only by about 30%, presumably through decreasing prostaglandin D2 (PGD2). We investigated whether niacin-induced flush in a rat model involves PGD2 and 5-HT, and the effect of certain flavonoids. EXPERIMENTAL APPROACH: Three skin temperature measurements from each ear were recorded with an infrared pyrometer for each time point immediately before i.p. injection with either niacin or a flavonoid. The temperature was then measured every 10 min for 60 min. KEY RESULTS: Niacin (7.5 mg per rat, equivalent to a human dose of 1750 mg per 80 kg) maximally increased ear temperature to 1.9+/-0.2 degrees C at 45 min. Quercetin and luteolin (4.3 mg per rat; 1000 mg per human), administered i.p. 45 min prior to niacin, inhibited the niacin effect by 96 and 88%, respectively. Aspirin (1.22 mg per rat; 325 mg per human) inhibited the niacin effect by only 30%. Niacin almost doubled plasma PGD2 and 5-HT, but aspirin reduced only PGD2 by 86%. In contrast, luteolin inhibited both plasma PGD2 and 5-HT levels by 100 and 67%, respectively. CONCLUSIONS AND IMPLICATIONS. Niacin-induced skin temperature increase is associated with PGD2 and 5-HT elevations in rats; luteolin may be a better inhibitor of niacin-induced flush because it blocks the rise in both mediators.

Anti-chemokine therapy for inflammatory diseases.

Chemokines are inflammatory proteins acting via G-protein coupled chemokine receptors that trigger different signaling pathways. Monocyte chemoattractant protein-1 (CCL2/MCP-1) and regulated on activation, normal T expressed and secreted (CCL5/RANTES) are the two major members of the CC chemokine beta subfamily. The roles of RANTES and MCP-1 are emerging in regulating the recruitment of inflammatory cells into tissue during inflammation. The inhibition of MCP-1 and RANTES with corresponding antibodies or other inhibitors may provide benefits in different clinical scenarios including cancer, inflammation, CNS disorders, parasitic disease, autoimmune and heart diseases. RANTES and MCP-1 may represent targets for diagnostic procedures and therapeutic intervention, and may be useful as a prognostic factor in the above diseases.

Mast cell deficient W/Wv mice have lower serum IL-6 and less cardiac tissue necrosis than their normal littermates following myocardial ischemia-reperfusion.

Myocardial ischemia-reperfusion (IR) injury complicates all forms of coronary artery revascularization. Circulating interleukin-6 (IL-6) has been implicated in cell death following a variety of stimuli. Macrophages, platelets, neutrophils and the endothelium have been shown to release IL-6 after IR injury. Cardiac mast cells have been implicated in IR; however, their involvement has never been quantified. In this randomized, prospective study, we compared cardiac tissue susceptibility and serum IL-6 changes between mast cell deficient (W/Wv) mice and their normal littermates (+/+). Twenty-eight male W/Wv mice (n=14) and their +/+ littermates (n=14) were anaesthetized with 2.5% isoflurane. The left coronary artery (LCA) was ligated for 30 minutes or a sham procedure was performed. After 6 hours of reperfusion, the animals were sacrificed. The muscle viability was assessed on fresh whole-mount slices by nitroblue tetrazolium (NBT) histochemical assay and serum IL-6 concentrations measured by ELISA. Cardiac muscle viability was significantly higher in W/Wv mice than the +/+ mice. Serum IL-6 levels were higher in the +/+ sham mice (465 +/- 32 pg/ml, n=6) than the W/Wv mice (185 +/- 31 pg/ml, n=6), p < 0.001. The IL-6 levels increased significantly after reperfusion only in the +/+ mice (698 +/- 41 pg/ml, n=8, p = 0.001), while it remained similar in the W/Wv mice (202 +/- 48 pg/ml, n=8, p = 0.783). These results show that the absence of mast cells reduces the myocardial damage associated with IR injury. Furthermore, there is an attenuation in the inflammatory response, as measured by serum IL-6 levels, following this local insult. This finding entertains the prospect of developing prophylactic therapy--targeting selective inhibition of cardiac mast cell activation, in clinical situations involving medical or surgical myocardial revascularization.

Intravesical suplatast tosilate (IPD-1151T) inhibits experimental bladder inflammation.

PURPOSE: Interstitial cystitis is a painful bladder disease characterized by urgency, frequency and variable inflammation but there is no curative therapy. Suplatast tosilate (IPD-1151T) is an immunoregulatory compound that decreases interstitial cystitis symptoms but to our knowledge its mechanism of action is unknown. We investigated the effect of intravesical IPD-1151T on mediator release from bladder explants in experimental cystitis. MATERIALS AND METHODS: A catheter was inserted into the bladder of female mice. After urine was emptied normal saline, carbachol (100 nM) or lipopolysaccharide (10 mg/ml) was introduced with or without 10-minute pretreatment with IPD-1151T. Urine was removed after 45 minutes for histamine and tumor necrosis factor-alpha assays. The bladder was removed after 4 hours, minced into 1 mm2 pieces and cultured with or without triggers overnight for mediator release. The effect of IPD-1151T was also tested on rat skin vascular permeability as well as on purified rat peritoneal mast cells and human cord blood derived mast cells. RESULTS: Carbachol significantly increased histamine release in urine (61.3% in 8 preparations, p<0.05) but not in explant medium. IPD-1151T inhibited this effect by 77%. Lipopolysaccharide induced a 350% urine histamine increase in 9 preparations (p<0.05) and a 300% tumor necrosis factor-alpha increase in explant medium. IPD-1151T inhibited the lipopolysaccharide induced medium tumor necrosis factor-alpha increase by 95% in 5 preparations (p<0.05). IPD-1151T did not inhibit rat skin vascular permeability or purified rat peritoneal mast cell activation by compound 48/80 or human cord blood derived mast cells by anti-IgE. CONCLUSIONS: IPD-1151T inhibits bladder release of histamine and tumor necrosis factor-alpha through a mechanism that does not appear to involve direct mast cell inhibition. These findings may justify a beneficial effect of IPD-1151T in interstitial cystitis.

Immunological activation of human umbilical cord blood mast cells induces tryptase secretion and interleukin-6, and histidine decarboxilase mRNA gene expression.

Allergy is the result of a complex immune cascade leading to the disregulated production of Th2 cytokines, the generation of allergen-specific IgE-producing B cells and the subsequent activation and degranulation of mast cells upon allergen challenge. Mast cell effector function significantly influences the quantity, duration and magnitude of most allergic reactions. Here, using isolated human umbilical cord blood mast cells (HUCBMC) from CD34+ cells, activated with anti-IgE (10 microg/ml) in culture, we found an augmented release of IL-6, tryptase and histamine (p < 0.01 compared with control). In addition, in these cells anti-IgE (10 microg/ml) activated the expression of histidine decarboxylase (HDC) and IL-6. In these studies we describe a new biological activity of anti-IgE in inducing histidine decarboxylase and IL-6, suggesting that this cytokine may have an important effect on allergic and inflammatory diseases mediated by mast cells. Moreover, with these data we confirm the immunoregulatory and inflammatory function of mast cells.