Histamine in the immune regulation of allergic inflammation

Histamine was the first mediator implicated in mechanisms of allergy, asthma, and anaphylactic shock because it has been discovered to mimic several features of these diseases. In addition to its well-characterized effects in the acute inflammatory and allergic responses, it was recently demonstrated that histamine regulates several essential events in the immune response. Histamine affects the maturation of immune system cells and alters their activation, polarization, chemotaxis, and effector functions. Histamine also regulates antigen-specific T(H)1 and T(H)2 cells, as well as related antibody isotype responses. Histamine binds to 4 different G protein-coupled receptors that transduce signals to cells through distinct pathways. The expression of these receptors on different cells and cell subsets is regulated, and apparently, the diverse effects of histamine on immune regulation are due to differential expression of 4 histamine receptors and their distinct intracellular signals. This article highlights novel discoveries in histamine immunobiology and discusses clinical findings or disease models that indicate immune regulation by histamine.     

GATA binding protein 3 overexpression and suppression significantly contribute to the regulation of allergic skin inflammation

GATA binding protein 3 (GATA3) is a key molecule regulating the balance in the ratio of type 1 helper T (Th1) cells to type 2 helper T (Th2) cells, which is thought to be indicative of the pathogenesis of allergic diseases such as asthma and atopic dermatitis. The aim of this study was to investigate the role of GATA3 in allergic skin inflammation. Transgenic (Tg) mice overexpressing human GATA3 (hGATA3) were produced by the microinjection of pCMV/hGATA3 constructs into fertilized mouse eggs. The hGATA3 gene was successfully expressed at the protein level in the lymph node and thymus of CMV/hGATA3 transfected cells and Tg mice. CMV/hGATA3 Tg mice showed a significant increase in the allergic skin inflammation response such as ear thickness, draining auricular lymph node (aLN) weight, epidermal thickness, inflammatory cell number and Th2 immunoglobulin (Ig) concentration compared to wild-type (WT) mice after phthalic anhydride (PA) treatment. Furthermore, the secretion of Th2 type cytokines was increased by PA treatment in CMV/hGATA3 Tg mice, while the secretion of Th1 type cytokine was suppressed under the same conditions. However, the increased levels of Th2 type cytokines in CMV/hGATA3 Tg mice were almost recovered by the down-regulation of GATA3 expression with D-pinitol treatment. Therefore, these findings suggest that GATA3 could be considered as a potential target regulating the mechanism responsible for the differences in allergic skin inflammation.     

Role of myeloid cells in the regulation of group 2 innate lymphoid cell-mediated allergic inflammation

Group 2 innate lymphoid cells (ILC2s) are an important component of the innate immune system that execute important effector functions at barrier surfaces, such as lung and skin. Like T helper type 2 cells, ILC2s are able to release high amounts of type 2 cytokines that are essential in inducing allergic inflammation and eliminating helminth infections. The past few years have contributed to our better understanding of the interactions between ILC2s and other cells of the immune system via soluble factors or in a cell–cell contact manner. Myeloid cells, including mononuclear leukocytes and polymorphonuclear leukocytes, are excellent sensors of tissue damage and infection and can influence ILC2 responses in the process of allergic inflammation. In this review, we summarize recent insights on how myeloid cell subsets regulate ILC2 activation with focus on soluble factors in the context of allergic inflammation.     

Expression and function of the ST2 gene in a murine model of allergic airway inflammation

BACKGROUND: We have recently reported that soluble ST2 protein levels are elevated in the sera of patients with asthma, and correlate well with the severity of asthma exacerbation. However, the role, function, and kinetics of soluble ST2 expression in asthma remain unclear. OBJECTIVE: The objective of the present study was to clarify the function and kinetics of soluble murine (m) ST2 expression in a murine asthma model. METHODS: We analyzed the kinetics of gene and protein expression of mST2 in sera or lung tissue after allergen (ovalbumin; OVA) challenge in a murine model of allergic airway inflammation, the effects of mST2 protein on OVA-induced Th2 cytokine production in vitro from splenocytes of sensitized mice, and the effects of soluble mST2 on Th2-dependent allergic airway inflammation by in vivo gene transfer of mST2. RESULTS: Serum mST2 protein levels increased to the maximal level 3 h after the allergen challenge, before serum IL-5 levels peaked. The mRNA expression of mST2 in lung tissue was induced after the allergen challenge, while that in the spleen was constitutively detected. Furthermore, pre-treatment with mST2 protein significantly inhibited the production of IL-4 and IL-5, but not IFN-gamma, from OVA-stimulated splenocytes in vitro, and intravenous mST2 gene transfer resulted in a drastic reduction in the number of eosinophils and in the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid, compared with those in response to transfer of non-coding plasmid vector or of lipid alone. CONCLUSION: These results suggest that increases in endogenous mST2 protein after allergen exposure may modulate Th2-mediated airway inflammation, and that in vivo gene transfer of mST2 can be applicable to use in a novel immunotherapy for allergic diseases.     

Potential autocrine regulation of interleukin-33/ST2 signaling of dendritic cells in allergic inflammation

This study identified a novel phenomenon that dendritic cells (DCs) produced interleukin (IL)-33 via Toll-like receptor (TLR)-mediated innate pathway. Mouse bone marrow–derived DCs were treated with or without microbial pathogens or recombinant murine IL-33. IL-33 mRNA and protein were found to be expressed by DCs and largely induced by several microbial pathogens, highly by lipopolysaccharide (LPS) and flagellin. Using two mouse models of topical challenge by LPS and flagellin and experimental allergic conjunctivitis, IL-33-producing DCs were observed in ocular mucosal surface and the draining cervical lymph nodes in vivo. The increased expression levels of myeloid differentiation primary-response protein 88 (MyD88), nuclear factor (NF)-κB1, NF-κB2, and RelA accompanied by NF-κB p65 nuclear translocation were observed in DCs exposed to flagellin. IL-33 induction by flagellin was significantly blocked by TLR5 antibody or NF-κB inhibitor quinazoline and diminished in DCs from MyD88 knockout mice. IL-33 stimulated the expression of DC maturation markers, CD40 and CD80, and proallergic cytokines and chemokines, OX40L, IL-4, IL-5, IL-13, CCL17 (C-C motif chemokine ligand 17), TNF-α (tumor necrosis factor-α), and IL-1β. This stimulatory effect of IL-33 in DCs was significantly blocked by ST2 antibody or soluble ST2. Our findings demonstrate that DCs produce IL-33 via TLR/NF-κB signaling pathways, suggesting a molecular mechanism by which local allergic inflammatory response may be amplified by DC-produced IL-33 through potential autocrine regulation.     

Heterotrimeric G protein signaling: role in asthma and allergic inflammation

Asthma and rhinitis are pathophysiologic conditions associated with a prototypical allergic response to inhaled allergens consisting of both neuromechanical and inflammatory components. Heptahelical receptors that bind guanosine triphosphate-binding proteins (G proteins), referred to as G protein-coupled receptors (GPCRs), have been intimately linked with asthma and allergic inflammation for many years. G protein signaling mediates responses throughout the immune, nervous, and muscular systems that might contribute to the pathogenesis of allergic processes and asthma. For example, GPCR agonists or antagonists are used as therapies for asthma either by promoting airway smooth muscle relaxation (beta2 adrenergic receptor agonists) or by inhibiting inflammation in the nasal mucosa and airways (cysteinyl leukotriene receptor antagonists). The focus of this review is to explore how downstream signaling cascades elicited by GPCR activation contribute to the allergic phenotype and the mechanism by which pharmaceuticals alter signaling to generate a therapeutic effect. We also discuss physiologic modulators of G protein signaling, such as regulator of G protein signaling proteins and G protein receptor kinases, inasmuch as they represent potential new therapeutic targets in the treatment of atopy and other inflammatory conditions.     

Possible mechanisms for the regulation of neutrophil apoptosis during allergic inflammation

The neutrophil-mediated inflammatory response is regulated via activation of the apoptosis program, which decreases the degree of tissue alteration. In rabbits with allergic inflammation a significant negative correlation was revealed between the intensity of neutrophil apoptosis and blood interferon-γ concentration. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 3, pp. 273–275, March, 2007     

Contribution of interleukin 17A to the development and regulation of allergic inflammation in a murine allergic rhinitis model

BackgroundInterleukin (IL) 17A, a key cytokine of T_H17 cells, is a well-known proinflammatory cytokine. Despite the important role of T_H17 cells in acute airway inflammation, the role of IL-17A in allergic rhinitis (AR) remains unclear.ObjectiveTo investigate the role of IL-17A in the allergic response in AR.MethodsWild-type BALB/c and IL-17A–deficient mice were immunized intraperitoneally and were challenged intranasally with ovalbumin. Allergic symptom scores, eosinophil infiltration, serum IgE level, and the levels of several cytokines in nasal lavage fluid and splenocyte supernatants were analyzed.ResultsIL-17A levels increased significantly more in ovalbumin-sensitized wild-type mice than in the negative control group. IL-17A–deficient mice showed a significant decrease in allergic symptoms, serum IgE levels, and eosinophil infiltration into the nasal mucosa compared with wild-type mice. IL-17A–deficient mice also showed decreased histamine and cysteinyl leukotriene release. Bone marrow–derived mast cells from IL-17A–deficient mice showed significantly lower degranulation and secretion of tumor necrosis factor α. Moreover, IL-17A deficiency attenuated the IL-5 level in nasal lavage fluid and its production in response to ovalbumin but did not increase interferon γ production and its level in nasal lavage fluid. In addition, secretion of IL-17A from spleen cells induced the expression of proinflammatory cytokine messenger RNA in macrophages. The mean level of proinflammatory cytokines, including tumor necrosis factor α and IL-17, decreased in IL-17A–deficient mice.ConclusionThese results suggest that IL-17A may partly contribute to the development of nasal allergic inflammation in an AR animal model and regulate AR via the activation of proinflammatory cytokines and modulation of T_H2 cytokine.     

An unusual expression of a squamous cell marker, small proline-rich protein gene, in tracheobronchial epithelium: differential regulation and gene mapping.

An unusual expression of a putative squamous cell marker, small proline-rich protein (spr1), in mucociliary epithelial cells of conducting airways was demonstrated in a serum-free culture system. A cDNA clone was isolated from the cDNA library of monkey tracheobronchial epithelial (TBE) cells by differential hybridization. This cDNA clone, MT5, exhibited 98% homology to a DNA sequence obtained from human keratinocytes treated with either UV light or phorbol esters (T. Kartasova et al., 1988, Mol. Cell. Biol. 8:2195-2230). The predicted peptide of MT5 is unusual for its high content of proline (29%), glutamine (18%), and cysteine (9%) and its repeated PKVPEPC units. The level of spr1 mRNA in cultured cells was inhibited more than 90% by vitamin A. In contrast, phorbol 12-myristate 13-acetate (PMA) stimulated the level of spr1 mRNA by 3- to 8-fold. This differential regulation coincided with the effects of these chemicals on the cornification of cultured TBE cells. Using MT5 as a probe, we have localized the tracheal spr1 gene on the human chromosome 1 by a Southern blot analysis using a panel of human-rodent somatic cell hybrid DNAs. The gene was further sublocalized to bands q22-23 by in situ hybridization.     

Innate and adaptive type 2 immunity in lung allergic inflammation

Allergic inflammation is a type 2 immune disorder classically characterized by high levels of immunoglobulin E (IgE) and the development of Th2 cells. Asthma is a pulmonary allergic inflammatory disease resulting in bronchial hyper-reactivity. Atopic asthma is defined by IgE antibody-mediated mast cell degranulation, while in non-atopic asthma there is no allergen-specific IgE and more involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. Recently, protease allergens were shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses. In this review, we discuss the role of Th2 cytokines (IL-4 and IL-13) and innate immune cells (mast cells, basophils, ILC2s, and dendritic cells) in the cross-talk between innate and adaptive inflammatory responses.     

Thioredoxin in allergic inflammation

Thioredoxin (TRX) is a redox-active protein that regulates reactive oxidative metabolism and plays a crucial role in the antioxidant system in regulating the reduction/oxidation balance by scavenging reactive oxygen species, which is implicated in the mechanism of asthma. As for the mechanisms by which TRX exerts its beneficial effects, some studies have shown that TRX suppresses allergic inflammation in animal models of asthma. Recently, we reported that TRX directly modulated the chemotaxis of eosinophils, which have been shown to play a pivotal role in the mechanism of allergic airway inflammation, in the absence of T helper (Th)1 or Th2 cytokines. Further, serum TRX levels in patients with asthma were significantly increased in patients with attacks compared with those in the asymptomatic period. This review focuses on TRX in allergic reactions and discusses the physiological role of TRX.     

呼吸道合胞病毒不同感染时间对过敏性气道炎症反应的作用研究

目的:探讨呼吸道合胞病毒(RSV)不同感染模式对花粉诱导的气道过敏性炎症反应的影响。方法:用花粉抽提物JCP致敏BALB/c鼠,在致敏前或致敏后的不同时间点经鼻粘膜感染RSV。HE染色法分类肺泡灌洗液中炎症细胞类型并计数其数量;ELISA法检测血清中过敏原特异性抗体含量;细胞因子检测试剂盒检测肺组织细胞培养上清中IL-17和IL-5水平。结果:与对照JCP组相比,JCP致敏前RSV感染组肺组织炎症细胞浸润程度明显减轻,炎症细胞总数及嗜酸性粒细胞数量明显下降;血清IgE总量及JCP特异性IgE和IgG1抗体水平显著降低;肺组织淋巴细胞IL-17分泌水平升高,而IL-5分泌减少。与致敏前RSV感染模式不同,致敏后RSV感染无论是对JCP诱导的气道过敏性炎症反应,亦或对血清抗体水平和细胞因子分泌活性均无明显影响。结论:RSV不同感染模式对JCP诱导的过敏性气道炎症具有不同的作用特点,致敏前RSV感染降低过敏原诱导的气道炎症反应。     

Platelets and allergic inflammation

Irrefutable clinical evidence demonstrates the activation of platelets in allergic diseases, including asthma, allergic rhinitis, and eczema. Indeed, experimental models of allergic disease have now shown that platelets play a fundamental role in the tissue recruitment of leucocytes following exposure to allergens. Furthermore, the extravascular presence of platelets in lungs of patients with asthma, and in animal models of allergic lung inflammation suggests that platelets may also contribute directly to allergic inflammation, through alterations in lung function, or by modulating processes involved in airway wall remodelling. Despite significant platelet activation in patients with allergic diseases, it is of note that these patients have been described as having a mild haemostastic defect, rather than an increased incidence of thrombosis. This suggests a dichotomy exists in platelet activation during inflammation compared to haemostasis, and that hitherto undiscovered platelet activation pathways might be exploited to create novel anti‐inflammatory therapies without affecting the critical function of platelets in haemostasis.