Yin-Yang of IL-33 in Human Skin Mast Cells: Reduced Degranulation, but Augmented Histamine Synthesis through p38 Activation.

Mast cells (MCs) are the principal effector cells of IgE-mediated allergy. IL-33 is released by resident skin cells as alarmin upon tissue damage or allergen contact. Owing to their pronounced receptor expression, MCs are important targets of IL-33 action, but consequences for skin MCs are ill-defined, especially upon chronic exposure to IL-33. Mimicking the inflammatory milieu of skin disorders, we found that persistent exposure to IL-33 (over a 5-week period) strengthened skin MC numbers through accelerated cell-cycle progression and restriction of apoptosis. Conversely, IL-33 attenuated degranulation and FcεRI expression, potentially as a feedback to chronic "alarmin" exposure. Interestingly, the negative impact on histamine release was counterbalanced by amplified histamine production. Considering the clinical significance of histamine and scarce information on its regulation, we explored the molecular underpinnings. IL-33 induced swift phosphorylation of p38 and JNK (but not of ERK1/2 or AKT), and stimulated histidine decarboxylase expression. Combining pharmacological inhibition and kinase elimination by Accell-facilitated RNA interference in skin MCs revealed a p38-dependent, but JNK-independent mechanism. Collectively, IL-33 exerts multifaceted effects on cutaneous MCs at a post-maturation stage. The IL-33-skin MC axis may contribute to and balance inflammation in chronic skin disorders.

Shuang-Huang-Lian injection induces an immediate hypersensitivity reaction via C5a but not IgE.

Among traditional Chinese medicine injections, intravenous Shuang-Huang-Lian (IV-SHL) has the highest incidence of injection-induced immediate hypersensitivity reactions (IHRs). The precise mechanisms of IV-SHL-induced IHRs remain ambiguous. In this study, we investigated the mechanisms of SHL injection (SHLI)-induced IHRs. Our data showed that serum total IgE and mouse mast cell protease 1 (MMCP1) levels were higher in the SHLI antiserum; however, these effects of SHLI disappeared in the antibiotic-treated mice. SHLI caused intraplantar vasopermeability and shock during the first local or systemic injection. SHLI-induced nonallergic IHRs were attributed to its intermediate fraction F2 (the extract of Lonicerae Japonicae Flos and Fructus forsythiae), and could be blocked by antagonists for histamine or C5a, rather than PAF or C3a. Eight constituents of F2 were able to directly activate C5 to promote local vasopermeability at the mg/mL level. In conclusion, SHLI-induced IHRs are not mediated by IgE. SHLI or its F2 can directly activate blood C5. Subsequently, C5a is likely to provoke histamine release from its effector cells (e.g., mast cells and basophils), indicating that histamine is a principal effector of IHRs induced by SHLI.

Evaluating the efficacy of epinastine ophthalmic solution using a conjunctivitis allergen challenge model in patients with birch pollen allergic conjunctivitis.

BACKGROUND: The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. METHODS: Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. RESULTS: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes. CONCLUSIONS: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis.

Factors influencing the formation of histaminol, hydroxytyrosol, tyrosol, and tryptophol in wine: Temperature, alcoholic degree, and amino acids concentration.

The validation of a HPLC-PDA-MS/MS chromatographic method for the quali/quantitative characterization of histaminol, hydroxytyrosol, tyrosol, and tryptophol in wine has been described and discussed. Four standards showed a good linearity with high correlation coefficient values (over 0.9989) and LOD and LOQ were 0.001-0.015 mg/L and 0.004-0.045 mg/L, respectively. Furthermore, this study reported how factors such as temperature, alcoholic degree, and amino acids concentration are able to influence the formation of these four alcohols in Monastrell wines. The quantification values of these alcohols has been detected both at the half and end of alcoholic fermentation, and at the end of malolactic fermentation. In relation to interactions between factors, several significant variations emerged (p ⩽ 0.001). The impact of amino acids supplementation in Monastrell must it has been demonstrated, mainly in regards to histaminol and tryptophol.

Histamine, histamine intoxication and intolerance

Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life

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Cystatin SN upregulation in patients with seasonal allergic rhinitis.

Seasonal allergic rhinitis (SAR) to the Japanese cedar, Cryptomeria japonica (JC) pollen is an IgE-mediated type I allergy affecting nasal mucosa. However, the molecular events underlying its development remain unclear. We sought to identify SAR-associated altered gene expression in nasal epithelial cells during natural exposure to JC pollen. We recruited study participants in 2009 and 2010 and collected nasal epithelial cells between February and April, which is the period of natural pollen dispersion. Fifteen patients with SAR-JC and 13 control subjects were enrolled in 2009, and 17 SAR-JC patients, 13 sensitized asymptomatic subjects (Sensitized), and 15 control subjects were enrolled in 2010. Total RNA was extracted from nasal epithelial cells and 8 SAR-JC patients and 6 control subjects in 2009 were subjected to microarray analysis with the Illumina HumanRef-8 Expression BeadChip platform. Allergen-stimulated histamine release was examined in the peripheral blood basophils isolated from patients with SAR. We identified 32 genes with significantly altered expression during allergen exposure. One of these, CST1 encodes the cysteine protease inhibitor, cystatin SN. CST1 expression in nasal epithelial cells was significantly upregulated in both the 2009 and 2010 SAR-JC groups compared with the control groups. Immunohistochemical staining confirmed the increased expression of CST1 in the nasal epithelial cells of SAR patients. Addition of exogenous CST1 to basophils inhibited JC allergen-stimulated histamine release in vitro. We propose that CST1 may contribute to inactivation of protease allergens and help re-establish homeostasis of the nasal membranes.

A nebulized complex traditional Chinese medicine inhibits Histamine and IL-4 production by ovalbumin in guinea pigs and can stabilize mast cells in vitro.

BACKGROUND: Traditional Chinese medicines have been used for anti-asthma treatment for several centuries in many Asian countries, and have been shown to effectively relieve symptoms. Our previous study demonstrated that a complex traditional Chinese medicine (CTCM) administered in nebulized form through the intratracheal route is effective against early-phase air-flow obstruction and can inhibit IL-5 production in ovalbumin (OVA)-sensitized guinea pigs. However, the antiasthmatic mechanisms of CTCMs are still unclear. METHODS: In this study, we examined the underlying mechanism of a CTCM that we used in our previous study in order to ascertain its function in the early-phase response to OVA challenge. RESULTS: We found that the inhibition of bronchoconstriction by the CTCM was attenuated by pretreatment with propranolol, suggesting that the CTCM has a bronchodilator effect that is associated with beta-adrenergic receptor. Our results also showed that the CTCM inhibited histamine and IL-4 secretion in the OVA-induced airway hypersensitivity in guinea pigs at 5 min post-OVA challenge, and in vitro study revealed that the CTCM is able to stabilize mast cells. CONCLUSION: In conclusion, our results suggested that the CTCM is a kind of bronchodilator and also a mast cell stabilizer. Our findings provide useful information regarding the possible mechanism of the CTCM, and show its potential for application in the treatment of allergenic airway disease.

Alpinia calcarata Roscoe: a potent antiinflammatory agent.

AIM OF THE STUDY: Alpinia calcarata Roscoe (Family: Zingiberaceae) rhizomes are often used in Sri Lankan traditional systems of medicine as a remedy for bronchitis, cough, respiratory ailments, diabetics, asthma and arthritis. Generally drugs that are used for arthritis have antinociceptive and antiinflammatory properties. However, validity of the antiinflammatory activity has not been scientifically investigated so far. Therefore, the aim of this study was to investigate the antiinflammatory potential of Alpinia calcarata rhizomes using hot water extract (AWE) and hot ethanolic extract (AEE). MATERIALS AND METHODS: The antiinflammatory activity of Alpinia calcarata was evaluated by use of the carrageenan-induced paw oedema model in rats. In addition, the mechanism/s by which Alpinia calcarata is mediated the antinflammatory activity was assessed by determining its effects on (a) membrane stabilizing, (b) antihistamine and (c) prostaglandin synthesis inhibition activity. RESULTS: All the tested doses of AWE and AEE (250, 500, 750, and 1000 mg/kg) produced a significant (P≤0.05) inhibition of the inflammation, most pronounced at 4h after the injection of carrageenan. The antiinflammatory effect induced by 500 mg/kg of AEE was superior than the reference drug, indomethacin at 4h. Inhibition of histamine and prostaglandin synthesis production is probable mechanisms by which Alpinia calcarata mediates its antiinflammatory action. CONCLUSION: These findings rationalize the traditional usage of Alpinia calcarata as an antiinflammatory agent for the first time.

Effect of Perilla frutescens var. acuta Kudo and rosmarinic acid on allergic inflammatory reactions.

Allergy is characterized by an overreaction of the immune system. Perilla frutescens leaf extract has been reported to exhibit antiallergic inflammatory activity. To investigate precisely the effect and mechanism of 30% ethanol extract powder of P. frutescens var. acuta Kudo (EPPF) and rosmarinic acid (RA), a component of EPPF in allergic rhinitis and rhinoconjunctivitis, the antiallergic effects of EPPF and RA were analyzed using in vivo and in vitro models. Cytokine production was analyzed by means of an enzyme-linked immunosorbent assay. Cytokine expression was analyzed via reverse transcription-polymerase chain reaction and Western blotting. Transcription factor and caspase-1 activity were analyzed by a luciferase assay and caspase-1 assay, respectively. The number of nasal, ear and eye rubs after an ovalbumin (OVA) challenge in OVA-sensitized mice was significantly higher than that in OVA-unsensitized mice. Increased number of rubs was inhibited by administration of EPPF or RA. Increased levels of IgE in the serum, spleen and nasal mucosa of OVA-sensitized mice were reduced by EPPF or RA administration. The histamine level was also reduced by EPPF or RA administration in the serum of OVA-sensitized mice. Protein levels and mRNA expressions of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α were inhibited by EPPF or RA administration in the nasal mucosa tissue or spleen of OVA-sensitized mice. In EPPF or RA-administered mice, the mast cell and eosinophil infiltration increase as caused by OVA-sensitization was decreased. In addition, EPPF or RA inhibited both cyclooxygenase-2 protein expression and caspase-1 activity in the same nasal mucosa tissue. In activated human mast cells, nuclear factor-kappa B (NF-κB)/Rel A and caspase-1 activation increased, whereas NF-κB/Rel A and caspase-1 activation was inhibited after a treatment of EPPF or RA. These results indicate that EPPF and RA ameliorate allergic inflammatory reactions such as allergic rhinitis and allergic rhinoconjunctivitis.

Targeting of histamine producing cells by EGCG: a green dart against inflammation?

The human body is made of some 250 different cell types. From them, only a small subset of cell types is able to produce histamine. They include some neurons, enterochromaffin-like cells, gastrin-containing cells, mast cells, basophils, and monocytes/macrophages, among others. In spite of the reduced number of these histamine-producing cell types, they are involved in very different physiological processes. Their deregulation is related with many highly prevalent, as well as emergent and rare diseases, mainly those described as inflammation-dependent pathologies, including mastocytosis, basophilic leukemia, gastric ulcer, Crohn disease, and other inflammatory bowel diseases. Furthermore, oncogenic transformation switches some non-histamine-producing cells to a histamine producing phenotype. This is the case of melanoma, small cell lung carcinoma, and several types of neuroendocrine tumors. The bioactive compound epigallocatechin-3-gallate (EGCG), a major component of green tea, has been shown to target histamine-producing cells producing great alterations in their behavior, with relevant effects on their proliferative potential, as well as their adhesion, migration, and invasion potentials. In fact, EGCG has been shown to have potent anti-inflammatory, anti-tumoral, and anti-angiogenic effects and to be a potent inhibitor of the histamine-producing enzyme, histidine decarboxylase. Herein, we review the many specific effects of EGCG on concrete molecular targets of histamine-producing cells and discuss the relevance of these data to support the potential therapeutic interest of this compound to treat inflammation-dependent diseases.

Inhibition of release of inflammatory mediators in rat peritoneal mast cells and murine macrophages by a Chinese herbal medicine formula (RCM-102).

RCM-102 is a Chinese herbal medicine formulation derived from a formula which was shown to be effective in treating seasonal allergic rhinitis (SAR) in a randomized placebo-controlled trial. The aim of this study was to investigate the in vitro effect of RCM-102 on the formation of inflammatory mediators, histamine, prostaglandin and nitric oxide, which are known to be involved in the pathophysiology of SAR. The effect of RCM-102 on histamine release was tested in compound 48/80-stimulated rat peritoneal mast cells. The effects of RCM-102 on the release of NO and prostaglandins (PGE(2)) and the expression of inducible NO synthase (iNOS) and COX-2 were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In rat peritoneal mast cells, RCM-102 significantly reduced the compound 48/80-induced histamine release. It also significantly reduced NO and PGE(2) production as well as the expression of COX-2 and iNOS in RAW 264.7 cells. These findings indicate that RCM-102 inhibits the formation of several allergic/inflammatory mediators and thus may be used for treating related conditions such as SAR. The actions of RCM-102 are likely to be contributed by the synergistic actions of individual herbal ingredients.

Lithospermi radix extract inhibits histamine release and production of inflammatory cytokine in mast cells.

Lithospermi radix (LR, Borraginaceae, the root of Lithospermum erythrorhizon Siebold. et Zuccarinii) is used in herbal medicine to treat such conditions as eczema, skin burns and frostbite. This study investigates the effects of LR on the anti-allergy mechanism. LR inhibited the release of histamine from rat peritoneal mast cells by compound 48/80 in a dose-dependent manner. LR orally administered at 6.59 mg/100 g also inhibited the anti-DNP IgE-induced passive cutaneous anaphylaxis reaction. LR inhibited the PMA plus A23187-induced increase in IL-6, IL-8, and TNF-alpha expression in HMC-1 cells. In addition, LR also inhibited nuclear factor-kappa B (NF-kappaB) activation and I kappaB-alpha degradation. These results show that LR had an inhibitory effect on the atopic allergic reaction. Furthermore, the in vivo and in vitro anti-allergic effect of LR suggests possible therapeutic applications of this agent for inflammatory allergic diseases.

Critical role of protein kinase C betaII in activation of mast cells by monomeric IgE.

Accumulating evidence suggests that IgE-mediated activation of mast cells occurs even in the absence of antigen, which is referred to as "monomeric IgE" responses. Although monomeric IgE was found to induce a wide variety of responses, such as up-regulation of the FcepsilonRI, survival, cytokine production, histamine synthesis, and adhesion to fibronectin, it remains to be clarified how mast cells are activated in the absence of antigen. It has been controversial whether monomeric IgE responses are mediated by a similar signaling mechanism to antigen stimulation, although recent studies suggest that IgE can induce the FcepsilonRI aggregation even in the absence of antigen. In this study, we focused on the role of conventional protein kinase C (cPKC), since this response is suppressed by a specific inhibitor for cPKC. Monomeric IgE-induced Ca(2+) influx was not observed in a mouse mastocytoma cell line, which lacks the expression of PKCbetaII, although Ca(2+) influx induced by cross-linking of the FcepsilonRI was intact. Transfection of PKCbetaII cDNA was found to restore the Ca(2+) influx induced by monomeric IgE in this cell line. Furthermore, the dominant negative form of PKCbetaII (PKCbetaII/T500V) significantly suppressed the Ca(2+) influx, histamine synthesis, and interleukin-6 production in another mouse mast cell line, which is highly sensitive to monomeric IgE. Expression of PKCbetaII/T500V was found not to affect the antigen-induced responses. These results suggest that PKCbetaII plays a critical role in monomeric IgE responses, but not in antigen responses.

Alterations of mast cell mediator production and release by gamma-linolenic and docosahexaenoic acid.

The purpose of our investigations was to evaluate the supposed beneficial effects of gamma-linolenic (GLA) and docosahexaenoic acid (DHA) in a canine mastocytoma cell line (C2) as a model for canine atopic dermatitis. Cells were cultured in a basic medium (DEH) and in DEH supplemented with 14.3 microM GLA (DEH-GLA) or 14.3 microM DHA (DEH-DHA) for 8 days. Chymase and tryptase activity, as well as histamine and prostaglandin (PG)E(2) release were measured. To stimulate histamine and PGE(2) release, cells were incubated with the wasp venom peptide mastoparan (50 microM) for 30 min. GLA increased tryptase activity and decreased histamine release after C2 stimulation. DHA diminished PGE(2) production in activated C2. These results support the prescription of GLA- and DHA-enriched diets to reduce inflammatory signs in canine atopic dermatitis.

Biogenic amines in restructured beef steaks as affected by added walnuts and cold storage.

This article evaluates changes in biogenic amines and how these relate to microbiological growth in chilled, fresh restructured beef steaks containing transglutaminase as a cold binding agent and different amounts of walnut. Added walnut and chilling favored higher total and lactic acid bacteria counts during storage, whereas Enterobacteriaceae were not affected. The highest initial biogenic amine concentrations were identified as spermidine, spermine, and tyramine. Both added walnut and cold storage generally favored the formation of amines (tyramine, histamine, putrescine, and cadaverine), which was more obviously apparent by the end of the storage period. Agmatine, on the other hand, was not generally affected by the walnut.

Green tea epigallocatechin-3-gallate is an inhibitor of mammalian histidine decarboxylase.

(-)-epigallocatechin-3-gallate, an antiproliferative and antiangiogenic component of green tea, has been reported to inhibit dopa decarboxylase. In this report,we show that this compound also inhibits histidine decarboxylase, the enzymic activity responsible for histamine biosynthesis. This inhibition was proved by a double approach, activity measurements and UV-Vis spectra of enzyme-bound pyridoxal-5'-phosphate. At 0.1 mM (-)-epi-gallocatechin-3-gallate, histidine decarboxylase activity was inhibited by more than 60% and the typical spectrum of the internal aldimine form shifted to a stable major maximum at 345 nm, suggesting that the compound causes a stable change in the structure of the holoenzyme. Since histamine release is one of the primary events in many inflammatory responses, a new potential application of (-)-epigallocatechin-3-gallate in prevention or treatment of inflammatory processes is suggested by these data.

Pycnogenol inhibits the release of histamine from mast cells.

Oxygen derived free radicals are now increasingly regarded as a primary force of tissue destruction and also have the ability to release histamine from mast cells. Pycnogenol is an extract of the bark of French maritime pine (Pinus pinaster) containing bioflavonoids with a potent ability to scavenge free radicals. Therefore Pycnogenol was investigated for inhibition of histamine release from rat peritoneal mast cells. In addition, its effects were compared with sodium cromoglycate, a known inhibitor of histamine release from the mast cell. Rat peritoneal mast cells were isolated and purified by differential centrifugation and cells pooled from 3-4 animals were suspended at approximately 10(6) cells/mL buffered salt solution. Histamine release was induced by compound 48/80 or the calcium ionophore A-23187 and estimated from supernatant following extraction and by fluorimetric methods. Pycnogenol produced a concentration dependent inhibition of histamine release induced by the two secretagogues. Its inhibitory effect on mast cell histamine release was favourably comparable to sodium cromoglycate.

Effects of histamine H3 receptor agonist and antagonist on histamine co-transmitter expression in rat brain.

The histaminergic H3-receptor (H3R) controls histamine synthesis and release in the tuberomamillary nucleus. We evaluated the effects of stimulating or blocking of H(3)R on glutamate-decarboxylase 67 kDa (GAD-67) and galanin mRNA expression, two histamine co-transmitters.After in situ hybridization histochemistry (ISHH), we observed a colocalization of 100% between histidine decarboxylase (HDC) and GAD-67 or H3R and of 80 to 97% with galanin. Adult rats received an H3R agonist ((R)alpha-Methylhistamine) or antagonist (ciproxifan) and were sacrificed 1 or 3 hours later. Treatment effects on HDC, galanin and GAD-67 mRNA were studied by quantitative ISHH on serial sections. Treatment with the H3R agonist known to decrease histamine neuron activity initially reduced HDC and galanin gene expression but an inverse change, presumably reflecting a compensatory mechanism, was observed after 3 h on both markers. In contrast, the H3R antagonist known to activate histamine neurons, had opposite effects on the two markers, suggesting that co-transmitters are submitted to independent control mechanisms. Furthermore, GAD-67 mRNA levels were not significantly modified by these treatments.

Allisonella histaminiformans gen. nov., sp. nov. A novel bacterium that produces histamine, utilizes histidine as its sole energy source, and could play a role in bovine and equine laminitis.

When cattle and horses are fed large amounts of grain, histamine can accumulate in the gastrointestinal tract, and this accumulation can cause an acute inflammation of the hooves (laminitis). When ruminal fluid from dairy cattle fed grain supplements was serially diluted in anaerobic MRS medium containing histidine (50 mM), histamine was detected at dilutions as high as 10(-7). The histidine enrichments were then transferred successively in an anaerobic, carbonate-based medium (50 mM histidine) without glucose. The histamine producing bacteria could not be isolated from the rumens of cattle fed hay; however, histamine producing bacteria could be isolated the feces of cattle fed grain and the cecum of a horse. All of the histamine producing isolates had the same ovoid morphology. The cells stained Gram-negative and were resistant to the ionophore, monensin (25 microM). The doubling time was 110 min, and the yield was 1.5 mg cell protein per mmol histidine. The G+C content was 46.8%. Lysine was the only other amino acid used, but lysine did not allow growth if histidine was absent. Because carbohydrate and organic acid utilization was not detected, it appeared that the isolates used histidine decarboxylation as their sole mechanism of energy derivation. 16s rRNA gene sequencing indicated that the isolates were most closely related to low G+C Gram-positive bacteria (firmicutes), but similarities were < or = 94%. Because the most closely related bacteria (Dialister pneumonsintes, Megasphaera elsdenii and Selenomonas ruminantium) did not produce histamine from histidine, we propose that these histamine producing bacteria be assigned to a new genus, Allisonella, as Allisonella histaminiformans gen. nov., sp. nov. The type strain is MR2 (ATCC BAA610, DSM 15230).