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Theoharis C Theoharides

Publications and source records attributed to Theoharis C Theoharides.

At least 19 recordsLinked to original sources
PubMed2007

Corticotropin-releasing hormone and the blood-brain-barrier.

Increased blood-brain-barrier (BBB) permeability precedes any clinical or pathologic signs and is critical in the pathogenesis of multiple sclerosis (MS) and brain metastases. CD4+ TH1 cells mediate demyelination in MS, but how they get sensitized and enter the brain to induce brain inflammation remains obscure. TH2 cytokines associated with allergic disorders have recently been implicated in MS, while genes upregulated in MS plaques include the mast cell-specific tryptase, the IgE receptor (Fc-epsilon-RI) and the histamine-1 receptor. Mast cell specific tryptase is elevated in the CSF of MS patients, induces microvascular leakage and stimulates protease-activated receptors (PAR), leading to widespread inflammation. BBB permeability, MS and brain metastases appear to worsen in response to acute stress that leads to the local release of corticotropin-releasing hormone (CRH), which activates brain mast cells to selectively release IL-6, IL-8 and vascular endothelial growth factor (VEGF). Acute stress increases BBB permeability that is dependent on CRH and mast cells. Acute stress shortens the time of onset of experimental alleric encephalomyelitis (EAE) that does not develop in W/W mast cell deficient or CRH -/- mice. Brain mast cell inhibition and CRHR antagonists offer novel therapeutic possibilities.

Animals↗
PubMed2006

Inhibitory effect of quercetin on tryptase and MCP-1 chemokine release, and histidine decarboxylase mRNA transcription by human mast cell-1 cell line.

Mast cells are important in reactions of allergic disease and are also involved in a variety of neuroinflammatory diseases. Mast cells can be immunologically activated by IgE through their Fc receptors, as well as by neuropeptides and cytokines to secrete mediators. Here we used a human mast cell-1 (HMC-1) cell line cultured and treated with a physiological activator, anti-IgE, and a nonphysiological activator, calcium ionophore A23187, for tryptase and MCP-1 generation and transcription of histidine decarboxylase. We used quercetin, a potent antioxidant, cytoprotective and anti-inflammatory compound capable of inhibiting histamine and some cytokines released from several cell types, as an inhibitor of immunological and nonimmunological stimulus for mast cells. In this study quercetin inhibits, in a dose-response manner, tryptase and MCP-1. Moreover, using RT-PCR quercetin inhibited the transcription of histidine decarboxylase, the rate-limiting enzyme responsible for the generation of histamine from histidine, and MCP-1. Our data suggest that quercetin is an important and good candidate for reducing the release of pro-inflammatory mast cell mediators activated by physiological and nonphysiological stimulators.

Antioxidants↗
PubMed2006

Secondary anetoderma associated with mastocytosis.

BACKGROUND: Mastocytosis represents a wide spectrum of proliferative disorders of mast cells in the bone marrow, skin and/or internal organs. The most common manifestation is urticaria pigmentosa (UP), which is characterized by small or large brown-red maculopapules on the skin. Occasionally, elastic and collagen fibers in the lesions degenerate and result in a lax area of skin termed anetoderma. METHODS: We report a 21-year-old male patient with multiple cutaneous anetodermic lesions, present since infancy, at UP sites confirmed with histochemistry. RESULTS: Urinary N-methyl 24-hour histamine levels were elevated, but serum tryptase levels were within normal limits. Radiologic examination of long bones was unremarkable, as well as all other blood results. UP biopsy showed absence of epidermal involvement and increased number of mast cells located perivascularly. There was fragmentation of elastic fibers in the papillary dermis. CONCLUSIONS: A patient with multiple cutaneous anetodermic lesions, presented since infancy, led to the diagnosis of UP. Such an association is rare and raises intriguing questions concerning the pathogenesis of anetoderma.

Adult↗
PubMed2006

Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process.

Many skin disorders are associated with increased numbers of activated mast cells and are worsened by stress; however, the mechanism underlying these processes is not understood. Corticotropin-releasing hormone (CRH) is secreted under stress from the hypothalamus, but also in the skin, where it induces mast cell activation and vascular permeability. We investigated the effect of CRH in a number of animal models by using i.v. Evans blue extravasation as a marker of vascular permeability. Intradermal CRH is among the most potent peptides at 100 nM, its effect being nearly comparable to that of neurotensin (NT). Pretreatment of skin injection sites with the NT receptor antagonist SR48692 blocks CRH-induced vascular permeability, which is diminished in NT-/- mice, implying that NT is necessary for the effect of CRH. CRH and NT precursor mRNA are shown to be expressed in both dorsal root ganglia and skin, whereas the latter also expresses mRNA for prohormone convertase 5, an enzyme that cleaves pro-NT into its active form. We also show that the effect of both CRH and NT is absent in W/W(v) mast cell-deficient mice; however, only a fraction of skin mast cells express CRH receptors, as shown by FACS analysis of CRH receptor (CRHR) and c-kit double-positive disaggregated mouse skin mast cells. These findings suggest that CRH induces skin vascular permeability through NT acting on mast cells and that both peptides should be considered in the pathogenesis of skin disorders exacerbated by stress.

Animals↗
PubMed2006

Theophylline as 'add-on' therapy to cetirizine in patients with chronic idiopathic urticaria. A randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Chronic urticaria is a prevalent condition associated with substantial disability. Its pathogenesis is not clearly understood and is divided into autoimmune and chronic idiopathic urticaria (CIU). We investigated if the non-specific phosphodiesterase inhibitor theophylline could provide additional benefit to the histamine-1 receptor (H-1R) antagonist cetirizine in CIU. METHODS: This was a double-blind, placebo-controlled, parallel study. Patients were randomized to receive either cetirizine and theophylline (200 mg twice daily; group A, 67 subjects) or cetirizine and placebo for 6 months (group B, 67 subjects). Group A patients took theophylline for 6 more months. Response was assessed by visual analog scale (VAS) and treatment effectiveness score (TES). Blood theophylline levels were also determined at visit t=1 and t=7. RESULTS: The study was completed by 54 of the 67 patients (80.6%) in group A and 51 of the 67 patients (76.1%) in group B. The physician VAS values for group A were lower after t=3, while the patient VAS values were decreased after t=2. The physician and patient TES values in group A were statistically higher (p<0.05) at all time points except for t=1. At least 1 month of theophylline addition was necessary to obtain statistically significant benefit over cetirizine, and reducing theophylline by 50% during phase 2 did not alter this benefit. Pruritus values were reduced, but not statistically significant. CONCLUSIONS: Addition of theophylline to conventional H-1R antagonists was well tolerated without any adverse effects and provided considerable additional benefit in the management of CIU.

Adolescent↗
PubMed2006

Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin.

Mast cells are involved in allergic reactions, but also in innate immunity and inflammation. Crosslinkage of mast cell Fc immunoglobulin E receptors (FcvarepsilonRI) by multivalent antigen triggers secretion of granule-stored mediators, as well as de novo synthesis of cytokines, including interleukin (IL)-6. We showed recently that the proinflammatory cytokine IL-1 stimulates human leukemic mast cells (HMC-1) and human umbilical cord blood-derived cultured mast cells (hCBMCs) to release newly synthesized IL-6 without tryptase in the absence of degranulation. Here, we investigated several signal-transduction pathways activated by IL-1 leading to IL-6 production by HMC-1 and hCBMCs. We also investigated the effect of the flavonol quercetin that was recently shown to strongly inhibit IL-6 secretion in response to allergic stimulation from hCBMCs.IL-1 stimulated p38, but did not activate extracellular signal-regulated kinase (ERK) or c-jun N-terminal kinase (JNK); it also did not activate protein kinase C (PKC) isozymes alpha, beta, mu and zeta, except for PKC-theta, which was phosphorylated. The p38 inhibitor SB203580 and the PKC inhibitors Calphostin C and Gö6976 completely inhibited IL-1-induced IL-6 production. Quercetin 1-100 microM inhibited IL-1-induced IL-6 secretion, p38 and PKC-theta phosphorylation in a dose-dependent manner. These results indicate that IL-1-stimulated IL-6 production from human mast cells is regulated by biochemical pathways distinct from IgE-induced degranulation and that quercetin can block both IL-6 secretion and two key signal transduction steps involved.

Carbazoles↗
PubMed2006

Neuroimmunology of stress: skin takes center stage.

Like few other organs, the skin is continuously exposed to multiple exogenous and endogenous stressors. Superimposed on this is the impact of psychological stress on skin physiology and pathology. Here, we review the "brain-skin connection," which may underlie inflammatory skin diseases triggered or aggravated by stress, and we summarize relevant general principles of skin neuroimmunology and neuroendocrinology. Specifically, we portray the skin and its appendages as both a prominent target of key stress mediators (such as corticotropin-releasing hormone, ACTH, cortisol, catecholamines, prolactin, substance P, and nerve growth factor) and a potent source of these prototypic, immunomodulatory mediators of the stress responses. We delineate current views on the role of mast cell-dependent neurogenic skin inflammation and discuss the available evidence that the skin has established a fully functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis as an independent, local stress response system. To cope with stress-induced oxidative damage, the skin and hair follicles also express melatonin, probably the most potent neuroendocrine antioxidant. Lastly, we outline major, as-yet unmet challenges in cutaneous stress research, particularly in the study of the cross-talk between peripheral and systemic responses to psychological stress and in the identification of promising molecular targets for therapeutic stress intervention.

Animals↗
PubMed2006

The critical role of mast cells in allergy and inflammation.

Mast cells are well known for their involvement in allergic and anaphylactic reactions, but recent findings implicate them in a variety of inflammatory diseases affecting different organs, including the heart, joints, lungs, and skin. In these cases, mast cells appear to be activated by triggers other than aggregation of their IgE receptors (FcepsilonRI), such as anaphylatoxins, immunoglobulin-free light chains, superantigens, neuropeptides, and cytokines leading to selective release of mediators without degranulation. These findings could explain inflammatory diseases, such as asthma, atopic dermatitis, coronary inflammation, and inflammatory arthritis, all of which worsen by stress. It is proposed that the pathogenesis of these diseases involve mast cell activation by local release of corticotropin-releasing hormone (CRH) or related peptides. Combination of CRH receptor antagonists and mast cell inhibitors may present novel therapeutic interventions.

Animals↗
PubMed2005

Corticotropin-releasing hormone induces vascular endothelial growth factor release from human mast cells via the cAMP/protein kinase A/p38 mitogen-activated protein kinase pathway.

Mast cells are involved in allergic reactions but also in innate immunity and inflammation. Corticotropin-releasing hormone (CRH), the key regulator of the hypothalamic-pituitary-adrenal axis, also has proinflammatory effects, apparently through mast cells. We showed recently that CRH selectively stimulates human leukemic mast cells and human umbilical cord blood-derived mast cells to release newly synthesized vascular endothelial growth factor (VEGF) without release of either preformed mediators or cytokines. This effect was mediated through the activation of CRH receptor-1 and adenylate cyclase with increased intracellular cAMP. However, the precise mechanism by which CRH induces VEGF secretion has not yet been defined. Here, we show that CRH-induced VEGF release was dose-dependently inhibited by the specific protein kinase A inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89) or the p38 mitogen-activated protein kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) but not by the specific inhibitor 2'-amino-3'-methoxyflavone (PD98059) of mitogen-activated protein kinase kinase, the upstream kinase of the extracellular signal-regulated protein kinase (ERK) or the c-Jun N-terminal kinase (JNK) inhibitor 1,9-pyrazoloanthrone anthra-(1,9-cd)pyrazol-6(2H)-one (SP600125). Furthermore, CRH significantly increased protein kinase A activity, which could be mimicked by the cell-permeable cAMP analog 8-bromo-cAMP, and was blocked by H89 or the adenylate cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CRH also induced rapid phosphorylation of p38 MAPK, which was mimicked by 8-bromo-cAMP and was inhibited by H89 or SB203580. CRH did not stimulate ERK or JNK phosphorylation and did not increase intracellular calcium levels. These results indicate that CRH induces VEGF release in human mast cells via selective activation of the cAMP/protein kinase A/p38 MAPK signaling pathway, thereby providing further insight into the molecular mechanism of how CRH affects the release of a key proinflammatory mediator.

Adenine↗
PubMed2005

Neuroimmunoendocrine circuitry of the 'brain-skin connection'.

The skin offers an ideally suited, clinically relevant model for studying the crossroads between peripheral and systemic responses to stress. A 'brain-skin connection' with local neuroimmunoendocrine circuitry underlies the pathogenesis of allergic and inflammatory skin diseases, triggered or aggravated by stress. In stressed mice, corticotropin-releasing hormone, nerve growth factor, neurotensin, substance P and mast cells are recruited hierarchically to induce neurogenic skin inflammation, which inhibits hair growth. The hair follicle is both a target and a source for immunomodulatory stress mediators, and has an equivalent of the hypothalamus-pituitary-adrenal axis. Thus, the skin and its appendages enable the study of complex neuroimmunoendocrine responses that peripheral tissues launch upon stress exposure, as a basis for identifying new targets for therapeutic stress intervention.

Animals↗
PubMed2005

Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor.

Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1alpha, 1beta, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2alpha (but not R2beta or R2gamma) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF-alpha release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress.

Blotting, Western↗
PubMed2005

Mast cell tryptase: a new biomarker in patients with stable coronary artery disease.

Mast cells may participate actively in the inflammatory process of atherosclerotic plaques by releasing proteolytic enzymes and various other pro-inflammatory substances. We hypothesized that increased levels of mast cell tryptase, could be an important biomarker in patients with stable coronary artery disease (CAD). We measured tryptase in 102 patients without acute coronary syndromes undergoing cardiac catheterization. Patients with significant CAD [> or =50% stenosis in > or =1 artery (n=66)] had significantly higher serum tryptase than patients with normal angiography (n=13) or non-significant CAD [<50% stenosis (n=23)]. The median, 25th and 75th percentiles for tryptase in these two groups were 8.38 (6.4 and 10.7)mug/L versus 6.78 (5.61 and 9.72) microg/L, p=0.014. Patients in the highest quartile of tryptase levels had a 4.3-fold risk for CAD [Odds ratio (OR): 4.3; 95% confidence interval (CI): 1.08-17.19; p=0.04]. In a multivariate regression analysis, tryptase remained an independent predictor for CAD along with age (OR: 1.178; 95% CI: 1.021-1.359, p=0.025). High circulating tryptase levels may be a result of chronic low-grade inflammatory activity present in atherosclerotic plaques. Tryptase measurements may emerge as a novel way of identifying asymptomatic patients with CAD, and represent a new biomarker of therapeutic efficacy in patients with CAD.

Aged↗
PubMed2005

The role of mast cells in migraine pathophysiology.

Mast cells are critical players in allergic reactions, but they have also been shown to be important in immunity and recently also in inflammatory diseases, especially asthma. Migraines are episodic, typically unilateral, throbbing headaches that occur more frequently in patients with allergy and asthma implying involvement of meningeal and/or brain mast cells. These mast cells are located perivascularly, in close association with neurons especially in the dura, where they can be activated following trigeminal nerve, as well as cervical or sphenopalatine ganglion stimulation. Neuropeptides such as calcitonin gene-related peptide (CGRP), hemokinin A, neurotensin (NT), pituitary adenylate cyclase activating peptide (PACAP), and substance P (SP) activate mast cells leading to secretion of vasoactive, pro-inflammatory, and neurosensitizing mediators, thereby contributing to migraine pathogenesis. Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines. A better understanding of brain mast cell activation in migraines would be useful and could lead to several points of prophylactic intervention.

Animals↗
PubMed2005

Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells.

Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which -- the flavonols, inhibits histamine and some cytokine release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory mediator release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 microM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-alpha was inhibited by 82-93% at 100 microM quercetin and kaempferol, and 31-70% by myricetin and morin. Tryptase release was inhibited by 79-96% at 100 microM quercetin, kampferol and myricetin, but only 39% by morin; histamine release was inhibited 52-77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose-response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC theta). Flavonol inhibition of IgE-mediated proinflammatory mediator release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC theta signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases.

Calcium↗
PubMed2005

Corticotropin-releasing hormone receptor-1 and histidine decarboxylase expression in chronic urticaria.

Certain skin disorders, such as contact dermatitis and chronic urticaria, are characterized by inflammation involving mast cells and worsen by stress. The underlying mechanism of this effect, however, is not known. The skin appears to have the equivalent of a hypothalamic-pituitary-adrenal (HPA) axis, including local expression of corticotropin-releasing hormone (CRH) and its receptors (CRH-R). We have reported that acute stress and intradermal administration of CRH stimulate skin mast cells and increase vascular permeability through CRH-R1 activation. In this study, we investigated the expression of CRH-R1, the main CRH-R subtype in human skin, and the mast cell related gene histidine decarboxylase (HDC), which regulates the production of histamine, in normal and pathological skin biopsies. Quantitative real time PCR revealed that chronic urticaria expresses high levels of CRH-R1 and HDC as compared to normal foreskin, breast skin and cultured human keratinocytes. The lichen simplex samples had high expression of CRH-R1, but low HDC. These results implicate CRH-R in chronic urticaria, which is often exacerbated by stress.

Adult↗