Reviews and Feature Articles: Rostrum
Histamine in the immune regulation of allergic inflammation,☆☆

https://doi.org/10.1067/mai.2003.1585Get rights and content

Abstract

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 TH1 and TH2 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. (J Allergy Clin Immunol 2003;112:15-22.)

Section snippets

Synthesis and metabolism of histamine

Histamine is synthesized by decarboxylation of histidine by L -histidine decarboxylase (HDC), which is dependent on the cofactor pyridoxal-5′-phosphate.2 Mast cells and basophils are the major source of granule-stored histamine, where it is closely associated with the anionic proteoglycans and chondroitin-4-sulfate. Histamine is released when these cells degranulate in response to various immunologic and nonimmunologic stimuli. In addition, several myeloid and lymphoid cell types (dendritic

Histamine receptors, agonists, and antagonists

Histamine exerts its effects by activating histamine receptors (HRs), of which 4 subtypes (HR1, HR2, HR3, and HR4) are recognized (Table I).

. Histamine receptors

Histamine receptorsExpressionActivated intracellular signalsG proteins
HR1Nerve cells, airway and vascular smooth muscles, hepatocytes, chondrocytes, endothelial cells, neutrophils, eosinophils, monocytes, DCs, T cells, B cellsCa2+, cGMP, phospholipase D, phospholipase A2, NF-κBGq/11
HR2Nerve cells, airway and vascular smooth muscles,

Immune regulation by histamine in allergic inflammation

The interaction of histamine with HR1 mediates a variety of effects, such as vasodilatation, bronchial smooth muscle contraction, mucus secretion, and pruritus, which lead to bronchial obstruction, increased vascular permeability, nasal blockade, sneezing, and itchy wheals and flares in urticaria.22 Although the classical effects of histamine are emphasized in allergy, an increasing amount of evidence suggest that it influences several immune-inflammatory and effector functions.23

Histamine and hr2 in peripheral T-cell tolerance

Considerable evidence has emerged to suggest that histamine participates in the immune regulation of the inflammatory response in several diseases. Peripheral T-cell tolerance characterized by immune deviation to regulatory-suppressor T cells represents a key event in the control of specific immune response during allergen-specific immunotherapy.52 Although multiple suppressor factors, including contact-dependent or contact-independent mechanisms, might be involved, IL-10 and transforming

Conclusion

Historical data and recent studies indicate an essential role of histamine in the immune dysregulation of allergy, asthma, autoimmunity, and malignancies. Histamine and so far 4 different HRs display a complex system with distinct functions of receptor subtypes and their differential expression, which changes according to the stage of cell differentiation, as well as microenvironmental influences. Although contrasting findings have been reported, HR1 activates the immune system cells,

References (73)

  • K Yoneda et al.

    Suppression by azelastine hydrochloride of NF-kappa B activation involved in generation of cytokines and nitric oxide

    Jpn J Pharmacol

    (1997)
  • M Idzko et al.

    Expression and function of histamine receptors in human monocyte-derived dendritic cells

    J Allergy Clin Immunol

    (2002)
  • R Gutzmer et al.

    Expression and function of histamine receptors 1 and 2 on human monocyte-derived dendritic cells

    J Allergy Clin Immunol

    (2002)
  • N Osna et al.

    Regulation of interleukin-10 secretion by histamine in TH2 cells and splenocytes

    Int Immunopharmacol

    (2001)
  • U Muller et al.

    Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy

    J Allergy Clin Immunol

    (2001)
  • HJ Nielsen et al.

    Possible role of histamine in pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists

    Med Hypotheses

    (1992)
  • JP White et al.

    Comparison of the effects of histamine H1- and H2-receptor agonists on large and small airways in normal and asthmatic subjects

    Br J Dis Chest

    (1987)
  • SK Field et al.

    Does medical antireflux therapy improve asthma in asthmatics with gastroesophageal reflux?: a critical review of the literature

    Chest

    (1998)
  • HH Dale et al.

    The physiological action of beta-imidazolylethylamine

    J Physiol (London)

    (1910)
  • Y Kubo et al.

    Regulation of histamine synthesis in mouse CD4+ and CD8+ T lymphocytes

    Inflamm Res

    (1999)
  • E Schneider et al.

    Histamine-producing cell-stimulating activity. Interleukin 3 and granulocyte-macrophage colony-stimulating factor induce de novo synthesis of histidine decarboxylase in hemopoietic progenitor cells

    J Immunol

    (1987)
  • T Yoshimoto et al.

    IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils

    Proc Natl Acad Sci U S A

    (1999)
  • M Dy et al.

    Histamine production during the anti-allograft response. Demonstration of a new lymphokine enhancing histamine synthesis

    J Exp Med

    (1981)
  • S Tanaka et al.

    Antigen-independent induction of histamine synthesis by immunoglobulin E in mouse bone marrow-derived mast cells

    J Exp Med

    (2002)
  • Y Abe et al.

    Histamine content, synthesis and degradation in human nasal mucosa

    Clin Exp Allergy

    (1993)
  • S Wilson et al.

    Orphan G-protein-coupled receptors: novel drug targets for the pharmeceutical industry

    Drug Des Discov

    (2000)
  • R Leurs et al.

    H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects

    Clin Exp Allergy

    (2002)
  • G Paesen et al.

    Tick histamine-binding proteins: isolation, cloning, and three dimensional structure

    Mol Cell

    (1999)
  • SJ Hill et al.

    International Union of Pharmacology. XIII. Classification of histamine receptors

    Pharmacol Rev

    (1997)
  • Y Aoki et al.

    Leukotriene B4 mediates histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells

    Am J Physiol

    (1998)
  • J Del Valle et al.

    Novel insights into histamine H2 receptor biology

    Am J Physiol

    (1997)
  • TW Lovenberg et al.

    Cloning and functional expression of the human histamine H3 receptor

    Mol Pharmacol

    (1999)
  • V Dimitriadou et al.

    Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen

    Clin Sci (Lond)

    (1994)
  • Y Zhu et al.

    Cloning, expression, and pharmacological characterization of a novel human histamine receptor

    Mol Pharmacol

    (2001)
  • FE Simons

    Comparative pharmacology of H1 antihistamines: clinical relevance

    Am J Med

    (2002)
  • E Vannier et al.

    Histamine enhances interleukin (IL)-1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist

    J Clin Invest

    (1993)
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    Supported by the Swiss National Foundation (grants 32.65661.01 and 31.65436.01).

    ☆☆

    Reprint requests: Cezmi A. Akdis, MD, Swiss Institute of Allergy and Asthma Research (SIAF), Obere Strasse 22, CH-7270 Davos, Switzerland.

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