Role of mast cells in the onset of IgE-mediated late-phase cutaneous response in mice

doi:10.1067/mai.2000.106778

Journal of Allergy and Clinical Immunology

Volume 106, Issue 1, Part 2, July 2000, Pages S91-S98

https://doi.org/10.1067/mai.2000.106778 Get rights and content

Abstract

Background: In mice that are passively sensitized to IgE, cutaneous antigen challenge produces a biphasic response with peaks at 1 and 24 hours after challenge. Objective: We investigated the role of mast cells in the IgE-mediated late-phase reaction in mice. Methods: We histologically and ultrastructurally investigated the morphologic changes of mast cells during the biphasic responses. Results: Degranulation of mast cells, which was observed between 4 and 24 hours after challenge, reached a peak at 8 hours. Piecemeal degranulation was seen during the immediate phase reaction. The number of IL-6–positive mast cells was increased after 4 hours in both IgE-sensitized and unsensitized mice, but positive cells showed a greater increase in sensitized mice and reached a peak after 8 hours. With in situ hybridization experiments, mast cells were positive for IL-6 messenger RNA at 6 hours after challenge. Conclusion: These findings indicate that anaphylactic degranulation of mast cells and the expression of IL-6 mRNA within 4 hours after antigen challenge are important for the onset of the late-phase allergic cutaneous reaction in mice. (J Allergy Clin Immunol 2000;106:S91-8.)

Section snippets

Mice

Female specific-pathogen–free BALB/c Cr Slic mice were obtained from Japan SLC (Shizuoka, Japan) and used at 8 to 10 weeks of age. They were housed in plastic cages in an air-conditioned room at 24°C, fed a standard laboratory diet, and given water as desired. All experiments were performed according to a guideline for the care and use of experimental animals made by the Japanese Association for Laboratory Animal Science in 1987.

Antibodies and other reagents

Monoclonal anti-dinitrophenol IgE was prepared from EC-1 cells.⁶ A

Ear thickness

The changes of ear thickness in passively sensitized mice showed 2 peaks after DNFB challenge (Fig l, A ) (Fig 1, B ).figureThe first peak was at 1 hour, and the second was at 24 hours after the challenge, which represented the IPR and LPR, respectively.

Histologic findings

At 30 minutes to 1 hour after the DNFB challenge, slight dermal edema and vasodilatation were observed in the ears (Fig 2, A and B ).figureAt 4 and 8 hours, mild inflammatory cell infiltration (mainly neutrophils and a few macrophages) and focal

DISCUSSION

This study showed that AND and the expression of IL-6 mRNA and protein by mast cells within 4 hours after antigen challenge were important steps preceding the allergic cutaneous LPR in mice.

Allergic individuals, who are exposed to an appropriate antigen challenge, experience an IPR followed several hours later by the LPR. In recent years, investigators have focused on the LPR, because it is felt that this inflammatory response, which not only involves mediators but also mobilization of various

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Upon allergen activation, preformed mediators stored in granules are released immediately by degranulation, mediating acute allergic response [35,36]. In contrast, newly synthesized cytokines and chemokines are released hours later, mediating late-phase allergic reactions [35,37]. Signaling pathways regulating degranulation are distinct from those controlling cytokine production: Activation of mitogen-activated protein kinases (MAPKs) including ERK1/2, p38 and JNK activate transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [38], activator protein-1 [39] and nuclear factor of activated T-cells [40] to potentiate cytokine production, while phospholipase C γ dependent elevation of free cytosolic Ca2+ concentration and protein kinase C signaling govern both degranulation and cytokine production [20].
Beyond their nutritional impact to colonic epithelial cells, the intestinal microbiota metabolite butyrate has pleotropic effects to host cells and is known for its beneficial effects on intestinal homeostasis and metabolism. However, it remains unclear how it modulates mast cell function. Here, we demonstrate that butyrate profoundly inhibited proliferation of mouse mastocytoma P815 cells through inducing cell cycle arrest and apoptosis, as well as decreasing c-Kit activation. In addition, butyrate increased early- and late-stage apoptotic P815 cells. In murine bone marrow-derived mast cells (BMMC), butyrate-suppressed FcεRI-dependent tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) release without affecting β-Hexosaminidase, but that was associated with decreased mitogen-activated protein kinase extracellular signal-regulated kinase 1/2, p38 and c-Jun N-terminal kinases activation. Butyrate treatment substantially enhanced histone 3 acetylation in both P815 and BMMC and decreased FcεRI-dependent mRNA expression of tnf-α and il-6 in BMMC, mimicking the effect of Trichostatin A, a known histone deacetylase inhibitor. Chromatin immunoprecipitation revealed that butyrate enhanced acetylation of the tnf-α and il-6 promoter regions but blocked RNA polymerase II binding to the promoters of tnf-α and il-6 genes, indicating suppressed transcription initiation. These phenotypes mimicked those of Trichostatin A treatment. In conclusion, butyrate inhibits cell proliferation and increases cell apoptosis in mastocytoma P815 cells and suppresses FcεRI-dependent cytokine production in murine primary BMMC, which are likely mediated by HDAC inhibition.
Progress in allergy signal research on mast cells: The role of histamine in immunological and cardiovascular disease and the transporting system of histamine in the cell
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Since its discovery in 1910, histamine has been regarded as one of the most important biogenic amines in the medical and biological fields. This article summarizes the information about the role of histamine in allergic situations, atherosclerosis, and autoimmune encephalomyelitis, especially focusing on our study with histidine decarboxylase gene knockout mouse. In the allergic bronchial asthma model, histamine positively controls eosinophilia but not bronchial hypersensitivity. Histamine is proved to be an important substance that controls body temperature and respiration in systemic anaphylaxis but its role in controlling blood pressure is minor. Histamine also plays a role in inducing atherosclerosis in the mouse model. We showed that experimental autoimmune encephalomyelitis (EAE) is significantly more severe in histamine-deficient mice with diffuse inflammatory infiltrates in the brain and cerebellum, including a prevalent granulocytic component. Histamine is mainly produced in mast cells and basophils in hematopoietic cells. We’ve shown that mast cells not only produce histamine, but also uptake it from the environmental medium and release it by allergic stimulants. The protein used for the plasma transport of histamine in basophils was identified as organic cation transporter (OCT3).
Role of T cells in IgE-dependent triphasic cutaneous reaction caused by dinitrofluorobenzene in the mouse ear: Participation of CD8<sup>+</sup> T cells
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Previous studies have suggested that mice passively sensitized with anti-dinitrophenol (DNP) monoclonal IgE antibody exhibit a triphasic cutaneous reaction with an immediate-phase response (IPR) at 1 h, a late-phase response (LPR) at 24 h and a very late-phase reaction (vLPR) at 8 days after challenge with 2,4-dinitrofluorobenzene. The present study was conducted to elucidate the role of T cells in this triphasic cutaneous reaction.
Mice were passively senseitized by an intravenous injection of anti-DNP monoclonal IgE antibody. Allergic cutaneous reaction was caused by painting an antigen on the ears of mice and measured an enlargement of the ears.
Whereas the magnitudes of IPR and LPR in BALB/c nu/nu T cell-deficient mice were similar to those in BALB/c +/+ mice, vLPR was not observed in nu/nu mice. In addition, FK 506 (3 and 5 mg/kg) and cyclosporin A (30 and 50 mg/kg) clearly suppressed the onset of vLPR without affecting IPR and LPR. Because these findings suggest the participation of T cells in the onset of vLPR, the character of the T cells was investigated by using anti-CD4 or anti-CD8 monoclonal antibody (mAb) and interleukin (IL)-4 and IL-5 receptor α chain gene-deficient mice. When mice were treated with anti-CD4 or anti-CD8 mAb, the magnitude of the vLPR was augmented by anti-CD4 mAb and suppressed by anti-CD8 mAb, without affecting IPR and LPR. Disruption of the IL-4 gene slightly suppressed IPR, LPR and vLPR, but the lack of the IL-5Rα chain gene did not affect these triphasic responses.
The present findings suggest that vLPR is mainly caused by CD8-positive T cells, probably Tc1 cells, and regulated by CD4-positive T cells.
Ultrastructural features of mast cells in picryl chloride (PCL)-induced contact dermatitis in IQI/Jic mice
2003, Experimental and Toxicologic Pathology
Mast cells are one of the major effector cells in the pathogenesis of allergic diseases such as contact dermatitis. In the present study, ultrastructural features of mast cells in contact dermatitis were examined. Namely, the ear of IQI/Jic mice was topically applied with picryl chloride (PCL) at 4 (1st), 11 (2nd), 18 (3rd) and 25 days (4th) after the sensitization with PCL to the abdominal skin. The changes in the ear swelling responses, total serum IgE levels and histology including mast cell numbers were similar to those of previous reports by our research group (Ikeda et al. 2000; Jung et al. 2001). Ultrastructurally, after the 1st application, a close spacial relationship between mast cells and neutrophils and phagocytosis of mast cell granules by neutrophils were observed. Mast cells generally contained non-fused swollen granules filled with altered contents with low electron density and showed an extrusion of membrane-free granules through membrane pores. In addition, interestingly, a few mast cells secreted membrane-bound granules into the dermis without leaving cell membrane damage. After the 4th application when the number of mast cells prominently increased and the total serum IgE level was greatly elevated, in addition to mast cells showing typical anaphylactic degranulation, many mast cells probably in the recovery process from degranulation and several immature mast cells characterized by well-developed Golgi apparatus, many ribosomes and a few electron-dense secretory granules in the peripheral cytoplasm were also observed at the same time. The present results clarified the ultrastructural features of mast cells in the course of PCL-induced contact dermatitis in IQI/Jic mice.
The control effect of histamine on body temperature and respiratory function in IgE-dependent systemic anaphylaxis
2002, Journal of Allergy and Clinical Immunology
Background: The systemic anaphylaxis reaction comprises various symptoms, including hypotension, changes in respiration pattern, and hypothermia. Objective: To elucidate the role of histamine in each of these symptoms, we induced the passive systemic anaphylaxis reaction in histidine decarboxylase gene knockout (HDC [-/-]) mice, which lack histamine. Methods: HDC(-/-) mice were generated by knocking out the HDC gene, which codes for the unique histamine-synthesizing enzyme. Twenty-four hours after the injection of IgE, HDC(+/+) and HDC(-/-) mice were injected with allergen and body temperature, blood pressure, and respiratory function were monitored in each mouse. Results: Blood pressure dropped in both the HDC(-/-) mice and the HDC(+/+) mice. In contrast, respiratory frequency dropped and the expiratory respiration time was elongated only in the HDC(+/+) mice. Body temperature was decreased in the HDC(+/+) mice and was practically unchanged in the HDC(-/-) mice. Histamine receptor antagonists blocked the body temperature drop in the HDC(+/+) mice. Intravenous histamine induced similar patterns of body temperature decrease in the HDC(+/+) mice and the HDC(-/-) mice. Mast cell-deficient W/W ^v mice did not show the decrease in body temperature; this suggests that the histamine that contributed to the decrease in body temperature was derived from mast cells. Conclusion: According to the results of this investigation, in the passive systemic anaphylaxis reaction, respiratory frequency, expiratory time, and body temperature are shown to be controlled by the activity of histamine, but its contribution to blood pressure is negligible. (J Allergy Clin Immunol 2002;110:298-303.)
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Role of mast cells in the onset of IgE-mediated late-phase cutaneous response in mice

Abstract

Section snippets

Mice

Antibodies and other reagents

Ear thickness

Histologic findings

DISCUSSION

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

The late phase of the immunoglobulin E mediated reaction: A link between anaphylaxis and common allergic disease?

J Allegy Clin Immunol

Cutaneous late-phase response to allergen: mediator release and inflammatory cell infiltration

J Clin Invest

Dexamethasone or cyclosporin A suppress mast cell-leukocyte cytokine cascades: multiple mechanisms of inhibition of IgE- and mast cell-dependent cutaneous inflammation in the mouse

J Immunol

The expression of murine cutaneous late phase reaction requires both IgE antibodies and CD4 T cells

Clin Exp Allergy

An immunopharmacological study of the biphasic allergic skin reaction in mice

Biol Pharm Bull

TNF-α participates in an IgE-mediated cutaneous reaction in mast cell deficient, WBB6F1-W/WVmice

Inflamm Res

Induction of eczematous skin reaction in experimentally induced hyperplastic skin of Balb/c mice by monoclonal anti-DNP IgE antibody: possible implications for skin lesion formation in atopic dermatitis

Int Arch Allergy Appl Immunol

Pharmacologic regulation of mediator generation and release from the murine bone marrow derived mast cell

Int Arch Allergy Appl Immunol

New insights into ″the riddle of the mast cells”: microenvironmental regulation of mast cell development and phenotypic heterogeneity

Lab Invest

IL-6 production by rat peritoneal mast cells is not necessarily preceded by histamine release and can be induced by bacterial lipopolysaccharide

J Immunol

Prostanoid enhancement of interleukin-6 production by rat peritoneal mast cells

J Immunol

Interferon β2/B cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells

Proc Natl Acad Sci USA

Interferon β₂/B cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells