Corticotropin-releasing hormone-receptor 2 is required for acute stress-induced bladder vascular permeability and release of vascular endothelial growth factor.

OBJECTIVE: To investigate the corticotropin-releasing hormone (CRH) receptor (CRH-R) requirement for the effect of acute stress on bladder vascular permeability and release of vascular endothelial growth factor (VEGF), as increasing evidence indicates that acute stress worsens certain inflammatory disorders, including interstitial cystitis/painful bladder syndrome (IC/PBlS), which is characterized by pain, variable bladder inflammation, increased expression of bladder vascular endothelial growth factor (VEGF), and many detrusor mast cells. MATERIALS AND METHODS: Bladders of normal C57BL/6, and C57BL/6- derived CRH-R1, CRH-R2 or double CRH-R1 + 2 knockout (-/-) female mice (10-12 weeks old) were catheterized under anaesthesia. After emptying the urine, normal saline was instilled with or without intravesical CRH-R antagonists in C57BL/6 mice before they were stressed by placing them in a restrainer for 30 min. Evans blue was injected in the tail vein before stress for the permeability experiments. The bladders from C57BL/6 or CRH-R -/- mice were then removed, minced into 1 mm(2) pieces and cultured overnight. Culture media were collected 24 h later for VEGF assay. C57BL/6 bladder was processed for CRH-R immunohistochemistry. RESULTS: Acute stress increased bladder vascular permeability in control C57BL/6 and CRH-R1 -/- mice, but not CRH-R2 -/- or CRH-R1+2 -/- mice. The CRH-R2 antagonist Astressin 2B, but not the CRH-R1 antagonist Antalarmin, inhibited stress-induced VEGF release from C57BL/6 mouse bladder explants. Stress could not induce a VEGF increase from bladder explants of CRH-R2 -/- or CRH-R1+2 -/- mice, but did so in CRH-R1 -/- mice. Bladder CRH-R2 immunoreactivity was detected in C57BL/6 bladders. CONCLUSIONS: Acute stress induces bladder vascular permeability and VEGF release that is dependent on CRH-R2. These findings suggest that CRH and VEGF might participate in the pathogenesis of IC/PBlS and provide for new therapeutic targets.

Mitochondrial uncoupling protein 2 inhibits mast cell activation and reduces histamine content.

Mast cells are immune effector cells that are involved in allergies and inflammation through the release of mediators such as histamine, PGs, and cytokines. Uncoupling protein 2 (UCP2) is a mitochondrial protein that inhibits insulin secretion from beta cells, possibly through down-regulation of reactive oxygen species production. We hypothesized that UCP2 could also regulate mast cell activation. In this study, we show that mouse bone marrow mast cells (BMMCs) and human leukemic LAD2 mast cells express UCP2. BMMCs from Ucp2(-/-) mice exhibited greater histamine release, whereas overexpression of UCP2 in LAD2 cells reduced histamine release after both allergic and nonallergic triggers. Ucp2(-/-) BMMCs also had elevated histamine content and histidine decarboxylase expression. Histamine content was reduced by overexpression of UCP2 or treatment with the mitochondrial-targeted superoxide dismutase-mimetic (TBAP) tetrakis(4-benzoic acid) porphyrin manganese(III). Furthermore, Ucp2(-/-) BMMCs also had greater production of both IL-6 and PGD(2) as well as ERK phosphorylation, which is known to regulate PG synthesis. Intradermal administration of substance P, an activator of skin mast cells, and challenge with DNP-human serum albumin after passive sensitization induced significantly greater vascular permeability in the skin of Ucp2(-/-) mice in vivo. Our results suggest that UCP2 can regulate mast cell activation.

Niacin-induced "flush" involves release of prostaglandin D2 from mast cells and serotonin from platelets: evidence from human cells in vitro and an animal model.

Niacin lowers serum cholesterol, low-density lipoprotein, and triglycerides, and it raises high-density lipoprotein. However, most patients experience cutaneous warmth and vasodilation (flush). Acetylsalicylic acid (ASA) can reduce this flush, presumably by decreasing prostaglandin D(2) (PGD(2)) release from macrophages. Here, we show that methylnicotinate induces significant PGD(2) release from human mast cells and serotonin from human platelets. Intradermal injection of methylnicotinate induces rat skin vasodilation and vascular permeability. Niacin increases plasma PGD(2) and serotonin in a rat model of flush. The phenothiazine prochlorperazine, the H(1), serotonin receptor antagonist cyproheptadine, and the specific serotonin receptor-2A antagonist ketanserin inhibit niacin-induced temperature increase by 90% (n = 5, p < 0.05), 90 and 50% (n = 3, p < 0.05), and 85% (n = 6, p = 0.0008), respectively, in this animal model. These results indicate that niacin-induced flush involves both PGD(2) and serotonin, suggesting that drugs other than ASA are required to effectively inhibit niacin-induced flush.

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.

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.

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.

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.

Interleukin-17 and the interleukin-17 family member network.

Interleukin-17 (now known as IL-17A), is a homodimer of two 155 amino acid chains secreted by CD4+ activated memory T cells (CD45+ RO+) and is available as a glycosylated 20- to 30-kDa homodimeric peptide. Human IL-17 shows amino acid sequence identity of 62.5 and 58% to the mouse and rat sequences, respectively. IL-17 can regulate the function of a variety of cell types, plays an important role in the maturation of hematopoietic progenitor cells, and induces production of proinflammatory mediators. Here, for the first time, we summarize the biological effects of IL-17 and its family members as important players of T cell-mediated immune responses and underline the important implications of this cytokine in inflammation and degenerative diseases.

Relation of serum levels of mast cell tryptase of left ventricular systolic function, left ventricular volume or congestive heart failure.

BACKGROUND: Activated mast cells (MC) present in the myocardium of patients with cardiomyopathy may contribute to left ventricular dilatation and systolic dysfunction. We sought to determine whether peripheral levels of tryptase, an MC-specific protease, are related to indices of left ventricular size and function, as well as congestive heart failure (CHF) or coronary artery disease (CAD). METHODS AND RESULTS: Serum tryptase was measured in 85 patients undergoing cardiac catheterization with left ventriculography and coronary angiography and examined in relation to left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), congestive heart failure (CHF), and angiographically evident CAD. Systemic tryptase levels were lower in patients with increased (>90 mL) LVEDV (6.2 [5.3-8.0] mcg/L versus 8.3 [6.6-10.3] mcg/L, P=.01) and in patients with CHF (6.2 [3.6-7.3] mcg/L versus 8 [6.2-10] mcg/L, P=.02) and tended to be lower in patients with depressed (<55%) LVEF (6.8 [5.2-9] mcg/L versus 8 [6.3-9.9] mcg/L, P=NS). Linear regression did not show a significant relationship between tryptase levels with either LVEF or LVEDV. Finally, tryptase levels were consistently elevated in relation to the presence of CAD. CONCLUSION: Despite increased numbers of MC in the myocardium of patients with cardiomyopathy, systemic levels of MC tryptase appear to be lower in relation to LV systolic dysfunction, LV dilatation, or clinical CHF. In contrast, the presence of angiographically significant CAD is associated with elevated systemic tryptase levels.

Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells.

Stress activates the hypothalamic-pituitary-adrenal axis through CRH, leading to production of glucocorticoids that down-regulate immune responses. However, acute stress also has proinflammatory effects. We previously showed that restraint stress, as well as CRH and its structurally related urocortin (Ucn), could activate mast cells and trigger mast cell-dependent vascular permeability. Here we show for the first time that human cord blood-derived cultured mast cells (hCBMC) at 10 wk, but not at 2 wk, are immunocytochemically positive for CRH and Ucn; human leukemic mast cells are weakly positive for both peptides. The ability of these mast cells to synthesize CRH and Ucn was confirmed by showing mRNA expression with RT-PCR. hCBMC (8-14 wk) synthesize and store 1-10 ng/106 cells (10-20 microg/g) of both CRH and Ucn detected by ELISA of cell homogenates. Stimulation of IgE-sensitized hCBMC with anti-IgE results in secretion of most CRH and Ucn. These findings indicate that mast cells are not only the target, but also a potential source of CRH and Ucn that could have both autocrine and paracrine functions, especially in allergic inflammatory disorders exacerbated by stress.

Azelastine inhibits secretion of IL-6, TNF-alpha and IL-8 as well as NF-kappaB activation and intracellular calcium ion levels in normal human mast cells.

BACKGROUND: Mast cells are involved in allergic inflammation by secreting histamine, proteases and several cytokines, including interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha) and IL-8. Certain histamine-1 receptor antagonists, such as azelastine present in the ophthalmic solution Optivar, have been reported to inhibit histamine and tryptase secretion, but its effect on inflammatory cytokine release from normal human umbilical cord blood-derived cultured mast cells (hCBMC) are not well known. METHODS: We investigated the effect of azelastine on the secretion of IL-6, TNF-alpha and IL-8 from hCBMC, as well as its possible mechanism of action. hCBMC sensitized with IgE were pretreated for 5 min with azelastine at 0.01, 0.1, 1, 3, 6, 12, 24, or 60 microM of Optivar, before stimulation with anti-IgE for 6 h. Optivar vehicle without azelastine was used as control. Cytokines were measured by ELISA, intracellular calcium levels by calcium indicators confocal, and nuclear factor-kappaB (NF-kappaB) by electromobility shift assay. RESULTS: Stimulation with anti-IgE led to substantial secretion of IL-6, TNF-alpha and IL-8. Preincubation for 5 min resulted in almost maximal inhibition with 6 microM azelastine for TNF-alpha (80%), with 24 microM for IL-6 (83%) and 60 microM for IL-8 (99%); the vehicle solution at the same concentrations as Optivar had no effect. Stimulation with anti-IgE increased intracellular Ca2+ level and induced NF-kappaB expression in hCBMC, which was inhibited by 24 microM azelastine. CONCLUSION: Azelastine inhibited hCBMC secretion of IL-6, TNF-alpha and IL-8, possibly by inhibiting intracellular Ca2+ ions and NF-kappaB activation. Azelastine may, therefore, be helpful in treating allergic inflammation.

The isoflavone genistein inhibits proliferation and increases histamine content in human leukemic mast cells.

Mast cells are involved in allergic inflammation and some rare disorders such as systemic mastocytosis and mast cell leukemia. Certain naturally occurring flavonoids have been shown to inhibit mast cell activation and promote maturation of secretory granules. Here, we report that the isoflavone genistein inhibited the growth of human leukemic mast cells (HMC-1) by 68.8, 51.6, and 30.2% at 10(-4), 10(-5), and 10(-6) M, respectively, at day 3 (p < 0.001). Genistein at 10(-4) M increased the histamine content per 2 x 10(5) cells at day 3 from 5.9 +/- 1.2 micrograms/mL to 11.1 +/- 1.3 micrograms/mL (n = 6; p < 0.0001). These results indicate that genistein can inhibit proliferation and induce maturation of HMC-1 cells.

IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells.

Fc epsilon RI cross-linkage in mast cells results in release of granule-associated mediators, such as histamine and proteases, as well as the production of numerous cytokines, including IL-6. Mast cells have been increasingly implicated in inflammatory processes where explosive degranulation is not commonly observed. Here, we show that IL-1 stimulates secretion of IL-6 without release of the granule-associated protease tryptase in normal human umbilical cord blood-derived mast cells (hCBMCs). IL-6 secretion stimulated by IL-1 in hCBMCs is potentiated by priming with IL-4 and reflects the higher levels of IL-6 secreted from human leukemic mast cell line (HMC-1). Stimulating HMC-1 cells by both IL-1 and TNF-alpha results in synergistic secretion of IL-6. IL-6 is de novo synthesized, as its secretion is blocked by inhibitors of transcription or protein synthesis. IL-1 does not increase intracellular calcium ion levels in either hCBMCs or HMC-1 cells, and IL-6 stimulation proceeds in the absence of extracellular calcium ions. Ultrastructural Immunogold localization shows that IL-6 is excluded from the secretory granules and is compartmentalized in 40- to 80-nm vesicular structures. Selective secretion of IL-6 from mast cells appears distinct from degranulation and may contribute to the development of inflammation, where the importance of IL-6 has been recognized.

High levels of intrauterine corticotropin-releasing hormone, urocortin, tryptase, and interleukin-8 in spontaneous abortions.

Stress induces CRH secretion that activates hypothalamic-pituitary-adrenal axis and is also abortogenic. In addition to hypothalamus, CRH and its analog urocortin (Ucn) are also secreted locally outside the brain where they activate mast cells leading to inflammation; however, the level of CRH and Ucn or mast cell mediators has not been examined in products of conception (POC). CRH and Ucn were measured by enzyme immunoassay, tryptase by fluoroenzyme immunoassay, and IL-8 by ELISA in POC of 7-9 wk gestation from Caucasian women; they were divided into group I with elective abortions (n = 4), group II with one spontaneous abortion (n = 12), and group III with at least two spontaneous abortions (n = 7). CRH, Ucn, tryptase, and IL-8 levels were higher (P < 0.05) in group III (8683 +/- 1201 pg/g, 7961 +/- 1499 pg/g, 1553 +/- 572 ng/g, and 8317 +/- 1874 pg/g, respectively) than group II (2561 +/- 314 pg/g, 2349 +/- 394 pg/g, 403 +/- 97 ng/g, and 3199 +/- 449 pg/g, respectively) and group I (163 +/- 162 pg/g, 328 +/- 327 pg/g, 72 +/- 31 ng/g, and 3681 +/- 931 pg/g, respectively). Immunostaining of POC showed significantly more tryptase in group III women. High POC levels of CRH and Ucn under stress in habitual spontaneous abortions may activate uterine mast cells to secrete abortogenic tryptase and IL-8.

Acute stress results in skin corticotropin-releasing hormone secretion, mast cell activation and vascular permeability, an effect mimicked by intradermal corticotropin-releasing hormone and inhibited by histamine-1 receptor antagonists.

BACKGROUND: Mast cells play an important role in allergic inflammation by releasing vasoactive molecules, proteases and cytokines. Corticotropin-releasing hormone (CRH) and its structural analogue urocortin (Ucn) were shown to trigger skin mast cell activation and vascular permeability. We investigated the effect of acute stress on rat skin vascular permeability and CRH secretion, as well as the effect of intradermal CRH, and that of two histamine-1 receptor antagonists, azelastine and olopatadine, on vascular permeability. METHODS: Rats were stressed by restraint and vascular permeability was assessed by extravasation of (99)Tc-gluceptate, while mast cell activation was determined by skin rat mast cell protease-1 (RMCP-1) content. Skin CRH content was evaluated by ELISA. The effect of intradermal injection of CRH and Ucn, as well as that of two histamine-1 receptor antagonists, azelastine and olopatadine, was assessed by Evan's blue extravasation. Purified rat peritoneal mast cells (RPMCs) were also pretreated with azelastine (24 microM) or olopatadine (133 microM) for 5 min before challenge with compound 48/80 (0.5 microg/ml) for 30 min. Histamine secretion was measured fluorometrically. Intracellular Ca(2+) ions were evaluated in RPMCs loaded with calcium crimson and stimulated with compound 48/80. RESULTS: Acute stress increased skin vascular permeability and CRH content, while it decreased RMCP-1. Intradermal injection of CRH or Ucn induced substantial Evan's blue extravasation that was inhibited by pretreatment with azelastine (24 microM) and olopatadine (133 microM). Both antihistamines also inhibited histamine release and intracellular increase of Ca(2+) ions from RPMCs stimulated by compound 48/80. CONCLUSIONS: These results indicate that acute stress increases skin CRH that can trigger mast cell-dependent vascular permeability, effects inhibited by certain histamine-1 receptor antagonists, possibly acting to reduce intracellular Ca(2+) ion levels.

IL-10, an inflammatory/inhibitory cytokine, but not always.

IL-10 has been previously called cytokine synthesis inhibiting factor, produced mostly by Th2 cells, macrophages and CD8+ cell clones. IL-10 is capable of inhibiting the synthesis of several cytokines from different cells, antigen or mitogen activated. IL-10 exerts its inhibition at the mRNA transcriptional and translational level. In addition, IL-10 is a co-stimulatory cytokine on activated T cells. For example, IL-10 inhibits NK cell activity, the production of Th1 cytokines, cytokines generated by peripheral blood mononuclear cells, and macrophage activity. On the other hand, IL-10 exerts immunostimulatory effects on B cells, cytotoxic T cell development and thymocytes. In mast cells derived from CD4+/CD133+ cells, IL-10 inhibits IL-6 and TNFalpha, and prostaglandin E(1) and E(2) induced by IL-6. Here, we report for the first time that IL-10 fails to inhibit tryptase and IL-6 from human mast cell-1 (HMC-1) and human umbilical cord blood-derived mast cells.

The effect of a herbal water-extract on histamine release from mast cells and on allergic asthma.

A water extract of a mixture of eight herbs (chamomile, saffron, anise, fennel, caraway, licorice, cardomom and black seed) was tested for its inhibitory effect on histamine released from rat peritoneal mast cells stimulated either by compound 48/80 or be IgE/anti-IgE. The effect of the herb extract was compared to that of the flavonoid quercetin. The herbal water-extract inhibited histamine released from chemically- and immunologically-induced cells by 81% and 85%, respectively; quercetin treated cells were inhibited by 95% and 97%, respectively. The clinical results showed significant improvements of sleep discomfort, cough frequency and cough intensity in addition to increased percentages of FEV1/FVC in patients suffering from allergic asthma, who used the herbal tea compared to those who used the placebo tea.

Flavones inhibit proliferation and increase mediator content in human leukemic mast cells (HMC-1).

OBJECTIVE: Mast cells are involved in allergic and inflammatory reactions. These cells are also increased in the bone marrow, skin, and other organs in systemic mastocytosis. Flavonoids are naturally occurring molecules with antioxidant, cytoprotective, and anti-inflammatory activities. Some flavonoids, like quercetin, inhibit the growth of certain malignant cells in culture. Quercetin also inhibits histamine release and induces accumulation of secretory granules in rat basophilic leukemia cells. METHOD: We investigated the effect of five flavonoids: flavone, kaempferol, morin, myricetin, and quercetin at 1, 10, and 100 microM on proliferation and secretory mediator content (beta-hexosaminidase, histamine, and tryptase) in human leukemic mast cells (HMC-1), the doubling time of which was about 2 d. RESULTS: Flavone and kaempferol at 100 microM inhibited cell proliferation over 80% on either day 3, 4, or 5 of culture. Quercetin showed this level of inhibition only on day 5, myricetin inhibited by 50% at days 3-5, whereas morin's inhibition was < 20%. All flavonoids (except morin) at 100 microm increased histamine and tryptase content, but not beta-hexosaminidase, equally at days 3 and 4 of culture quercetin also increased the development of secretory granules. CONCLUSION: These results indicate that certain flavonoids can inhibit HMC-1 proliferation, induce secretory granule development and the accumulation of mediators.

Interleukin-6 and mast cells.

Interleukin (IL) 6 is a pleiotropic cytokine (26 kDa) that originally was named interferon beta 2 or B cell-stimulating factor or differentiating B cell factor inducing immunoglobulin production. IL-6 is produced in many diseases. After secretion, IL-6 binds to its receptor IL-6R alpha (gp 80), the IL-6R alpha complex then recruits the signal-transducing beta-subunit (gp 130), which is the functional complex for signal transduction. In addition, activation of Th2 cells or mast cells also produce IL-6, which mediates immune responses, inflammation, acute phase responses, hematopoiesis, cancer, inflammatory bowel disease, etc. IL-6 also is a crucial cytokine for mast cell maturation. Human cord blood CD34+ cells differentiate and grow into mast cells in the presence of stem cell factor (SCF) and IL-6, causing increases in cell size, frequency of chymase positive cells, and intracellular histamine levels when compared with cells treated with SCF alone. Activated mast cells increase IL-6 mRNA associated with protein kinase C (PKC) activity. IL-6 also up-regulates histamine production rather than increases its storage and is an important inducing factor for the expression of immunoglobulin E (IgE) Fc epsilon RI.