Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation.

Although histamine is a well-known itch mediator, histamine H1-receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch. This review summarizes current knowledge of immune cell-derived itch mediators and neuronal response mechanisms, and discusses therapeutic agents that target these systems.

Re-sensitization of desensitized histamine H1 receptors in the human skin takes more than 18 hours.

BACKGROUND: It is known since the time of testing histamine on pieces of guinea pig's jejunum that histamine receptors can develop insensitivity. The aim was to find evidence for desensitization of histamine H1 receptors in the human skin in vivo and, if found, to study the time for such receptors to regain normal sensitivity. MATERIALS AND METHODS: A skin prick test with histamine (10 mg mL-1 ) was set in areas where a large histamine wheal was evoked 2, 6, 18, 24 or 72 hours earlier. A skin prick test with histamine (10 mg mL-1 ) was also set in an area where an allergen wheal was evoked 2 or 6 hours earlier. Heights, diameters and areas were measured on photographs of side views of plaster casts of the evoked skin elevations. RESULTS: Histamine wheals, called test wheals, in areas where large histamine wheals were evoked 2, 6 or 18 hours earlier, were smaller than histamine wheals, called initial wheals, in earlier non-stimulated areas. Test wheals from the 18 hours experiment were smaller than test wheals from the 72 hours experiment. Test wheals evoked in areas where allergen wheals were evoked 2 or 6 hours earlier were smaller than corresponding initial wheals. CONCLUSION: Histamine-evoked wheals and IgE-mediated allergic wheals reduce the sensitivity of histamine H1 receptors in the human skin. It takes between 18 and 72 hours to restore the sensitivity. Similarities between the development of histamine wheals in the human skin and histaminergic migraine with aura are discussed.

Interleukin-1 and histamine are essential for inducing nickel allergy in mice.

BACKGROUND: We previously reported that (a) lipopolysaccharide (LPS) is a potent adjuvant for inducing Nickel (Ni) allergy in mice at both the sensitization and elicitation steps, (b) LPS induces Interleukin-1 (IL-1) and histidine decarboxylase (HDC, the histamine-forming enzyme), and IL-1 induces HDC, (c) Ni allergy is induced in mast cell-deficient, but not IL-1-deficient (IL-1-KO) or HDC-KO mice. OBJECTIVE: To examine the roles of IL-1 and HDC (or histamine) and their interrelationship during the establishment of Ni allergy. METHODS: Ni (NiCl2 ) 1 mmol/L containing IL-1ß and/or histamine was injected intraperitoneally (sensitization step). Ten days later, test substance(s) were intradermally injected into ear pinnas (elicitation step), and ear swelling was measured. RESULTS: In wild-type mice, Ni + LPS or Ni + IL-1ß injection at sensitization step followed by Ni alone at elicitation step induced Ni allergy. In IL-1-KO, injection of Ni + IL-1ß (but not Ni + histamine) was required at both sensitization and elicitation steps to induce Ni allergy. In HDC-KO, Ni + IL-1ß + histamine at sensitization step followed by Ni + histamine at elicitation step induced Ni allergy. In histamine H1 receptor-deficient mice, IL-1ß induced HDC, but was ineffective as an adjuvant for inducing Ni allergy. In wild-type mice, injection into ear pinnas of Ni 10 mmol/L alone or Ni 1 mmol/L + LPS induced IL-1ß, HDC and a prolonged swelling of ear pinnas. In non-sensitized mice, injection of IL-1ß by itself into ear pinnas in IL-1-KO mice induced prolonged ear swelling. Ni augmented IL-1 production (both IL-1α and IL-1ß) and HDC induction in wild-type mice sensitized to Ni. CONCLUSIONS: In mice: (a) for inducing Ni allergy, IL-1 is essential at both the sensitization and elicitation steps, and HDC induction is involved in the effect of IL-1, (b) stimulation of H1 receptor is also essential for inducing Ni allergy at both sensitization and elicitation steps, and (c) the 'sensitization to Ni' state may be a state where tissues are primed for augmented production of IL-1α and/or IL-1ß in response to Ni. (within 300 words, now 300).

Phenothiazine antipsychotics exhibit dual properties in pseudo-allergic reactions: Activating MRGPRX2 and inhibiting the H1 receptor.

Phenothiazines are a class of antipsychotics that share the same tricyclic structure and are widely used in clinical settings. Adverse reactions from these drugs, however, have been regularly reported, with allergic skin reactions noted in some cases. Nevertheless, the mechanisms underlying anaphylaxis by these drugs have not been described. In the present study, we found that phenothiazine antipsychotics increased calcium mobilization and activated mast cells to release ß-hexosaminidase, histamine, and tumor necrosis factor-α via Mas-related G-protein-coupled receptor member X2 (MRGPRX2) in vitro. In addition, they induced histamine release in serum via Mrgprb2 in C57BL/6 mice without Evans blue extravasation or paw swell. Further experiments indicated these drugs had good interaction with the histamine H1 receptor (H1R) and show an anti-calcium mobilization effect on H1R-HEK293 cells, which confirmed a potential antagonist effect of these drugs on the H1R. The molecular docking and activity experiments indicated that the N-methyl substitution on the side chain of these drugs played a significant role in activating MRGPRX2, while the phenothiazine tricyclic ring was associated with the inhibiting effect on the H1R. Therefore, due to their dual properties of increasing histamine levels without obvious allergic symptoms, clinicians should be highly vigilant for damage from histamine accumulation and long-term inflammatory reactions during the clinical use of phenothiazine antipsychotics.

Sinomenine-induced histamine release-like anaphylactoid reactions are blocked by tranilast via inhibiting NF-κB signaling.

Zhengqing Fengtongning (ZQFTN), the pharmaceutical preparation of sinomenine (SIN) derived from the medicinal plant Sinmenium acutum, is well-known in China as an effective treatment for rheumatoid arthritis (RA). However, its histamine-release anaphylactoid reactions (HRARs) occur often in some patients. Therefore, it is desirable to establish effective clinical protocols to manage such HRARs. In the study, rat models with systemic HRARs and local HRARs of the skin were established. The level of vascular permeability and mast cell numbers was determined by quantitative analysis using Evans blue dye and histological assays. The levels of histamine, leukotriene B4 (LTB4) and IL-33 in plasma were detected by UHPLC-SPE-MS, ELISA and immunohistochemistry assays, respectively. The results demonstrated that SIN significantly induced both systemic and local HRARs in rats, showing significant decrease of body temperature, increases in vascular permeability in skin, injury of lung tissues and mast cell infiltration and IL-33 expression in skin and lung tissues. Mechanistic study showed that tranilast could prevent SIN-triggered HRARs via inhibition of H1 receptor gene expression and NF-κB signaling. Our findings provide evidence that mast cell membrane stabilizers and H1 receptor blockers effectively prevent SIN-induced HRARs, and cromolyn, cetirizine and tranilast can be used in the clinic for the management of HRARs induced by ZQFTN.

Histamine regulates murine primary dendritic cell functions.

OBJECTIVE AND DESIGN: The modulation of antigen uptake and activation of dendritic cells (DCs) by histamine may function as a regulator of inflammation. Therefore, we sought to determine the impact of histamine on antigen uptake by and activation of murine DCs. MATERIAL AND METHODS: DCs from spleen and lung were either identified by flow cytometry or were immunomagnetically enriched. Cells were stimulated with histamine, and the regulation of MHC-II and co-stimulatory molecule expression (CD80, CD86, and ICOS-L) and antigen uptake were quantified by flow cytometry. Individual contributions of the histamine receptor subtypes were determined by using the antagonists mepyramine (histamine H1-receptor: H1R), famotidine (H2R), and JNJ 7777120 (H4R). RESULTS: Histamine accelerated the uptake of soluble antigen via the H1R, H2R, and H4R in splenic DCs. Co-stimulatory molecule expression was enhanced already by enrichment procedures, thus, the analyses were performed in unseparated cell populations. Histamine enhanced the expression of CD86 and ICOS-L while expression of CD80 was unaffected. Antagonism at H1R, H2R, and H4R and at H1R and H4R reduced the histamine-induced enhanced expression of CD86 and ICOS-L, respectively. CONCLUSIONS: Histamine contributes to the regulation of the immunological synapse by stimulation of antigen uptake and activation of DCs via H1R, H2R, and H4R.

Histamine inhibits differentiation of skin fibroblasts into myofibroblasts.

Histamine and TGF-ß, major mediators secreted by mast cells, are involved in skin inflammation and play critical roles in the pathogenesis of systemic sclerosis. However, the roles of signaling mechanisms in the development of skin fibrosis remain largely unclear. Here we show that histamine suppressed the expression of α smooth muscle actin (αSMA), a marker of myofibroblasts, induced by TGF-ß1 in skin fibroblasts. Histamine H1-receptor (H1R), but not H2-receptor (H2R) or H4-receptor (H4R), was expressed on skin fibroblasts at both mRNA and protein levels. Interestingly, an H1R antagonist, but not H2R or H4R antagonists, antagonized the histamine-mediated suppression of αSMA expression by TGF-ß1. Correspondingly, phosphorylated Smad2 was detected after treatment with TGF-ß1, whereas the addition of histamine inhibited this phosphorylation. Taken together, histamine-H1R decreased TGF-ß1-mediated Smad2 phosphorylation and inhibited differentiation of skin fibroblasts into myofibroblasts.

The neglected role of histamine in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques accumulation and cognitive impairment. Both environmental factors and heritable predisposition have a role in AD. Histamine is a biogenic monoamine that plays a role in several physiological functions, including induction of inflammatory reactions, wound healing, and regeneration. The Histamine mediates its functions via its 4 G-protein-coupled Histamine H1 receptor (H1R) to histamine H1 receptor (H4R). The histaminergic system has a role in the treatment of brain disorders by the development of histamine receptor agonists, antagonists. The H1R and H4R are responsible for allergic inflammation. But recent studies show that histamine antagonists against H3R and regulation of H2R can be more efficient in AD therapy. In this review, we focus on the role of histamine and its receptors in the treatment of AD, and we hope that histamine could be an effective therapeutic factor in the treatment of AD.

Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity.

BACKGROUND: Histamine exerts diverse effects on immune regulation through four types of histamine receptors (HRs). Among them, type 1 receptor (H1R) plays an important role in allergic inflammation. Dendritic cells (DCs), which express at least three types of HRs, are professional antigen-presenting cells controlling the development of allergic inflammation. However, the molecular mechanisms involved in H1R-mediated NF-ĸB signaling of DCs remain poorly defined. METHODS: Bone-marrow (BM)-derived DCs (BM-DCs) were treated with H1R inverse agonists to interrupt basal H1R-mediated signaling. The crosstalk of H1R-mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay, NF-ĸB subunit analysis using Western blotting and TNF-α promoter activity using chromatin immunoprecipitation. RESULTS: Blockage of H1R signaling by inverse agonists significantly inhibited TNF-α and IL-6 production of BM-DCs. H1R-specific agonists were able to enhance TNF-α production, but this overexpression was significantly inhibited by NF-ĸB inhibitor. The H1R inverse agonist ketotifen also suppressed cellular NF-ĸB activity, suggesting crosstalk between H1R and NF-ĸB signaling in DCs. After comprehensive analysis of NF-ĸB subunits, c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs, which led to inhibition of the promoter activity of TNF-α. Finally, adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo. CONCLUSIONS: Our results suggest that c-Rel controls H1R-mediated proinflammatory cytokine production in DCs. This study provides a potential mechanism of H1R-mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation.

H(1)R expression by CD11B(+) cells is not required for susceptibility to experimental allergic encephalomyelitis.

The histamine H(1) receptor (Hrh1/H(1)R) was identified as an autoimmune disease gene in experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS). Previously, we showed that selective re-expression of H(1)R by endothelial cells or T cells in H(1)RKO mice significantly reduced or complemented EAE severity and cytokine responses, respectively. H(1)R regulates innate immune cells, which in turn influences peripheral and central nervous system CD4(+) T cell effector responses. Therefore, we selectively re-expressed H(1)R in CD11b(+) cells of H(1)RKO mice to test the hypothesis that H(1)R signaling in these cells contributes to EAE susceptibility. We demonstrate that transgenic re-expression of H(1)R by H(1)RKO-CD11b(+) cells neither complements EAE susceptibility nor T cell cytokine responses highlighting the cell-specific effects of Hrh1 in the pathogenesis of EAE and MS, and the need for cell-specific targeting in optimizing therapeutic interventions based on such genes.

The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice.

BACKGROUND: Although histamine H1 receptor (H1R) antagonists are commonly used to treat atopic dermatitis, the treatment is not always effective. The histamine H4 receptor (H4R) was recently described as important to the pruritus in dermatitis. Here, we investigated whether the combination of a H1R antagonist plus a H4R antagonist attenuates chronic dermatitis in NC/Nga mice. METHODS: Chronic dermatitis was developed by repeated challenges with picryl chloride on the dorsal back and ear lobes. The therapeutic effects of the H1R antagonist olopatadine and H4R antagonist JNJ7777120 on scratching and the severity of dermatitis were evaluated. In addition, the mechanisms responsible for the anti-allergic effects of H1R and/or H4R antagonism were examined using bone marrow-derived mast cells (BMMC) and keratinocytes. RESULTS: JNJ7777120 attenuated scratching behavior after a single administration and improved dermatitis, as assessed with clinical scores, pathology, and cytokine levels in skin lesions when administered repeatedly. These effects were augmented by combined treatment with olopatadine, having a similar therapeutic efficacy to prednisolone. JNJ7777120 inhibited dose-dependently the production of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 from antigen-stimulated BMMC. In addition, olopatadine reversed the histamine-induced reduction of semaphorin 3A mRNA in keratinocytes. CONCLUSION: Combined treatment with H1R and H4R antagonists may have a significant therapeutic effect on chronic dermatitis through the synergistic inhibition of pruritus and skin inflammation.

Histamine reduces susceptibility to natural killer cells via down-regulation of NKG2D ligands on human monocytic leukaemia THP-1 cells.

Natural killer (NK) group 2D (NKG2D) is a key activating receptor expressed on NK cells, whose interaction with ligands on target cells plays an important role in tumorigenesis. However, the effect of histamine on NKG2D ligands on tumour cells is unclear. Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A (MICA) and UL16-binding protein 1 on their surface, and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry. Interferon-γ augmented the surface expression of the NKG2D ligands, and this augmentation was significantly attenuated by histamine. The histamine H1 receptor (H1R) agonist 2-pyridylethylamine and H2R agonist dimaprit down-regulated the expression of NKG2D ligands, and activation of H1R and H2R signalling by A23187 and forskolin, respectively, had the same effect, indicating that the histamine-induced down-regulation of NKG2D ligands is mediated by H1R and H2R. Quantitative reverse transcription-PCR showed that mRNA levels of the NKG2D ligands and relevant microRNAs were not significantly changed by histamine. Histamine down-regulated the surface expression of endoplasmic reticulum protein 5, and inhibition of matrix metalloproteinases did not impair this down-regulation, indicating that proteolytic shedding was not involved. Instead, pharmacological inhibition of protein transport and proteasome abrogated it, and histamine enhanced ubiquitination of MICA. Furthermore, histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity. These results suggest that histamine down-regulates NKG2D ligands through the activation of an H1R- and H2R-mediated ubiquitin-proteasome pathway and consequently reduces susceptibility to NK cells.

Histamine H(1) receptor signaling regulates effector T cell responses and susceptibility to coxsackievirus B3-induced myocarditis.

Susceptibility to autoimmune myocarditis has been associated with histamine release by mast cells during the innate immune response to coxsackievirus B3 (CVB3) infection. To investigate the contribution of histamine H(1) receptor (H(1)R) signaling to CVB3-induced myocarditis, we assessed susceptibility to the disease in C57BL/6J (B6) H(1)R(-/-) mice. No difference was observed in mortality between CVB3-infected B6 and H(1)R(-/-) mice. However, analysis of their hearts revealed a significant increase in myocarditis in H(1)R(-/-) mice that is not attributed to increased virus replication. Enhanced myocarditis susceptibility correlated with a significant expansion in pathogenic Th1 and Vγ4(+) γδ T cells in the periphery of these animals. Furthermore, an increase in regulatory T cells was observed, yet these cells were incapable of controlling myocarditis in H(1)R(-/-) mice. These data establish a critical role for histamine and H(1)R signaling in regulating T cell responses and susceptibility to CVB3-induced myocarditis in B6 mice.

Albizia lebbeck suppresses histamine signaling by the inhibition of histamine H1 receptor and histidine decarboxylase gene transcriptions.

Histamine plays major roles in allergic diseases and its action is mediated mainly by histamine H(1) receptor (H1R). We have demonstrated that histamine signaling-related H1R and histidine decarboxylase (HDC) genes are allergic diseases sensitive genes and their expression level affects severity of the allergic symptoms. Therefore, compounds that suppress histamine signaling should be promising candidates as anti-allergic drugs. Here, we investigated the effect of the extract from the bark of Albizia lebbeck (AL), one of the ingredients of Ayruvedic medicines, on H1R and HDC gene expression using toluene-2,4-diisocyanate (TDI) sensitized allergy model rats and HeLa cells expressing endogenous H1R. Administration of the AL extract significantly decreased the numbers of sneezing and nasal rubbing. Pretreatment with the AL extract suppressed TDI-induced H1R and HDC mRNA elevations as well as [(3)H]mepyramine binding, HDC activity, and histamine content in the nasal mucosa. AL extract also suppressed TDI-induced up-regulation of IL-4, IL-5, and IL-13 mRNA. In HeLa cells, AL extract suppressed phorbol-12-myristate-13-acetate- or histamine-induced up-regulation of H1R mRNA. Our data suggest that AL alleviated nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through suppression of H1R and HDC gene transcriptions. Suppression of Th2-cytokine signaling by AL also suggests that it could affect the histamine-cytokine network.

Histamine receptor H1 signaling on dendritic cells plays a key role in the IFN-γ/IL-17 balance in T cell-mediated skin inflammation.

BACKGROUND: The diverse effects of histamine on immune regulation are a result of the differential expression and regulation of 4 histamine receptors. Many of the immediate allergic and inflammatory actions of histamine are mediated via the type 1 receptor (H1R). OBJECTIVES: We hypothesized that H1R was involved in the fine-tuning of the initiation of T cell-mediated skin pathology-that is, dermatitis. METHODS: The impact of the H1R invalidation on the development of skin inflammation was analyzed in a mouse model of atopic dermatitis. RESULTS: We show that H1r(-)/(-) mice developed reduced allergen-specific skin lesions. Lack of H1R expression on dendritic cells (DCs) led to diminished IL-12, upregulated IL-23, and IL-6 production upon allergen stimulation. H1R engagement on dendritic cells was necessary for DC activation and subsequent priming of effector IFN-γ(+)CD8(+) T cells. We demonstrate here that H1R blockade on DCs promotes generation of noneffector IL-17(+)CD8(+) T cells that are unable to initiate the skin inflammation. CONCLUSION: Our data identify that histamine signaling through the H1R on DCs is an important early event conditioning the quality of the skin effector immune response.

Innervation of histamine neurons in the caudal part of the arcuate nucleus of hypothalamus and their activation in response to food deprivation under scheduled feeding.

It has been well established that histaminergic neurons innervate densely the anterior hypothalamus and regulate several functions through the histamine H1 receptor (H1R). However, the physiological function of the histaminergic neurons in other regions including the posterior hypothalamus has not been fully investigated. Recently, we have found a selective c-Fos expression in the caudal part of the arcuate nucleus of the hypothalamus (cARC) by food deprivation under scheduled feeding in rats. In this study, we histochemically examined the correlation of this c-Fos expression with the activation of histaminergic neurons in this region using an anti-H1R antibody. Strong H1R immunoreactivity was observed in the perikarya of the c-Fos positive cells. Abundant histamine-containing fibers were also found in the cARC and in the area between the cARC and the tuberomammillary nucleus (TM), where the histaminergic neuronal cell bodies are exclusively distributed. Our morphological observations suggest that c-Fos expression in the cARC by food deprivation under scheduled feeding is caused by the activation of histaminergic neurons projected from the TM.

Antihistamines in the treatment of urticaria.

Most urticaria subtypes have a profound impact on patients' quality of life and performance. Effective treatment is thus required in all cases where the avoidance of eliciting factors and the elimination of underlying causes is not feasible. In nearly all subtypes histamine released by mast cells plays apredominant role. For symptomatic relief second generation nonsedatinghistamine H1 receptor (H1R)-antihistamines are, therefore, the first choice. However, double-blind controlled studies have shown that dosages required to achieve complete protection from urticaria symptoms may exceed those recommended for other diseases, e.g., allergic rhinitis. Therefore, the current guidelines suggest increasing the dosage up to fourfold, whereas alternative treatments should be reserved as add-on therapy for unresponsive patients.

Histamine stimulates interleukin-6 production through histamine H1 receptors in human amnion cells.

BACKGROUND/AIMS: Previous studies have stated that maternal allergic diseases are associated with increased risk of preterm labor/delivery, but the underlying mechanisms remain unclear. This study tested the hypothesis that histamine induces interleukin (IL)-6 production in amnion cells. METHODS: Using cultured human amnion cells, we examined expression of histamine receptors and effects of histamine on IL-6 production. RESULTS: Reverse transcription-polymerase chain reaction and Western blotting revealed expression of histamine H1 receptor (H1R) and H2 receptor (H2R) in human amnion. Histamine stimulation significantly increased concentrations of IL-6 in conditioned medium, as did tumor necrosis factor-alpha and IL-1beta in positive controls. In addition, the H1R antagonist olopatadine significantly blocked histamine-induced production of IL-6, whereas the H2R antagonist ranitidine did not. CONCLUSION: Histamine appears to induce IL-6 production through H1R in human amnion cells.

Synergy of TLR2 and H1R on Cox-2 Activation in Pulpal Cells.

Although pulp fibroblasts are a major cell type in dental pulp, their roles in microbial recognition and pulpal inflammation are not well-understood. Considering the pivotal role of Toll-like receptors (TLRs) in the recognition of micro-organisms, we hypothesized that TLRs on pulp fibroblasts may induce inflammatory signals in dental pulp. In human pulp fibroblasts, TLR2, 3, 4, and 5 were constitutively expressed. Stimulation of TLR2 and 3 induced the expression of pro-inflammatory genes such as CXCL10, CCL5, and/or Cox-2 in pulp fibroblasts. Interestingly, histamine synergistically activated TLR2-mediated Cox-2 expression and PGE(2) production. The synergistic effect of histamine is mediated by histamine receptor-1 (H1R). Studies on the intra-cellular signaling pathways revealed that p38 activation is required for the synergistic activation of Cox-2 by TLR2 and histamine. Analysis of these data suggests that TLR2 on pulp fibroblasts, in concert with H1R, can induce an inflammatory response during microbial infection in dental pulp.