Anti-inflammatory effect of β2-agonists: Inhibition of TNF-α release from human mast cells,☆☆,,★★,

https://doi.org/10.1016/S0091-6749(97)70280-XGet rights and content

Abstract

β2-Agonists inhibit the release of preformed mediators such as histamine and newly synthesized mediators such as prostaglandin D2 from mast cells. However, although mast cells have been identified as an important source of several cytokines including tumor necrosis factor-α (TNF-α), there is no information about their regulation by β2-agonists. Thus given the importance of TNF-α in inflammation and the widespread use of β2-agonists, we investigated the effect of long-acting (salmeterol) and short-acting (salbutamol) β2-agonists on the secretion of TNF-α from human skin mast cells. Treatment of mast cells with salmeterol or salbutamol (100 nmol/L) inhibited the IgE-dependent release of TNF-α (82% and 74%, respectively). Moreover, 2-hour treatment with salmeterol, isoproterenol, or salbutamol inhibited mast cell cytotoxicity against a TNF-α–sensitive cell line, WEHI-164, with an IC50 of 71, 50, and 29 nmol/L, respectively. Specificity for β-adrenergic receptors was shown with propranolol. The inhibitory effect of β2-agonists was observed after only 20 minutes of treatment but was lost by 24 hours after removal of salbutamol and isoproterenol (7% and 11% inhibition remaining, respectively). In contrast, the inhibition of TNF-α release was increased 1 hour after removal of salmeterol and remained significant 24 hours later. Furthermore, β2-agonists did not show tachyphylaxis for the inhibition of TNF-α release. Thus selective β2-agonists demonstrate anti-inflammatory activity by inhibiting the release of TNF-α from mast cells stimulated through their IgE receptor or by a tumor target cell. This inhibitory effect of β-agonists may be important in their mode of action in the treatment of allergic diseases. (J Allergy Clin Immunol 1997;100:825-31.)

Section snippets

Materials

Collagenase from Clostridium histolyticum type I, hyaluronidase (type 1-s) from bovine testes, protease type XIV from Streptomyces griseus, N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), (±)-isoproterenol, (±)-propranolol (β12 adrenergic receptor antagonist), and forskolin were purchased from Sigma Chemical Co. (St. Louis, Mo.). Isoproterenol, propranolol, and forskolin were dissolved in ascorbic acid (20 μg/ml), in water, in RPMI, and in 20 μl ethanol, respectively, and used

Effect of β2-agonists on histamine release from human skin mast cells

As a control for our studies on TNF-α release, we have compared the effect of salmeterol and isoproterenol on the release of histamine by human skin mast cells. Isolated and enriched human skin mast cells were sensitized with IgE, incubated with β2-agonists, salmeterol or isoproterenol, and stimulated with anti-human IgE antibody. The specific release of histamine from IgE-stimulated mast cells was 21% ± 3% (n = 14, the spontaneous release was always less than 5%). Treatment with isoproterenol

DISCUSSION

TNF-α is an important mediator of inflammatory responses.21 It plays a crucial role in the recruitment and stimulation of inflammatory cells.32 TNF-α is stored in mast cell granules20 and is actively synthesized and secreted by activated mast cells,33 macrophages,34 and other inflammatory cells.21 IgE-dependent activation increases the production of TNF-α by human lung and skin mast cells,28, 35 suggesting that TNF-α may have an important role in allergic reactions.

Although there was some

References (54)

  • R Grönneberg et al.

    Inhibitory effects of formoterol and terbutaline on the development of late phase skin reactions

    Clin Exp Allergy

    (1992)
  • PJ. Barnes

    Beta-adrenergic receptors and their regulation

    Am J Respir Crit Care Med

    (1995)
  • NM Munoz et al.

    Beta adrenergic modulation of formyl-methionine-leucine-phenylalanine stimulates secretion of eosinophil peroxidase and leukotriene C4

    J Pharmacol Exp Ther

    (1994)
  • M Didier et al.

    Regulation of interleukin-2 synthesis by cAMP in human T cells

    J Immunol

    (1987)
  • RD. Feldman

    β-Adrenergic receptor-mediated suppression of interleukin-2 receptors in human lymphocytes

    J Immunol

    (1987)
  • MK Church et al.

    Inhibition of IgE-dependent histamine release from human dispersed lung mast cells by anti-allergic drugs and salbutamol

    Br J Pharmacol

    (1987)
  • PR Butchers et al.

    Salmeterol: a potent and long-acting inhibitor of inflammatory mediator release from human lung

    Br J Pharmacol

    (1991)
  • Y Okayama et al.

    Comparison of the modulatory effect of ketotifen, sodium cromoglycate, procaterol and salbutamol in human skin, lung and tonsil mast cells

    Int Arch Allergy Immunol

    (1992)
  • G Nilsson et al.

    Mast-cell heterogeneity: structure and mediators

  • AE Redington et al.

    Role of mast cells and basophils in asthma

    Chem Immunol

    (1995)
  • PR Burd et al.

    Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines

    J Exp Med

    (1989)
  • P Bradding et al.

    Interleukin-4, -5, -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines

    Am J Respir Cell Mol Biol

    (1994)
  • K Arai et al.

    Cytokines: coordinators of immune and inflammatory responses

    Annu Rev Biochem

    (1990)
  • I Ohno et al.

    Production of tumor necrosis factor with IgE receptor triggering from sensitized lung tissue

    Am J Respir Cell Mol Biol

    (1990)
  • JR Gordon et al.

    Mast cells as a source of both preformed and immunologically inducible TNFα-/cachectin

    Nature

    (1990)
  • RM Strieter et al.

    Role of tumor necrosis factor-alpha in disease states and inflammation

    Crit Care Med

    (1993)
  • O Cromwell et al.

    Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1 beta and tumour necrosis factor alpha

    Immunology

    (1992)
  • Cited by (0)

    From the Department of Medicine, University of Alberta, Edmonton.

    ☆☆

    Supported by Glaxo Group Research Ltd., U.K., and the Medical Research Council of Canada. E.Y.B. is a Scholar of the Medical Research Council/Canadian Lung Association; A.D.B. is a Scholar of the Alberta Heritage Foundation for Medical Research and the Astra Chair in Asthma Research.

    Reprint requests: Dr. Elyse Bissonnette, Pulmonary Research Group, Department of Medicine, HMRC 574, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.

    ★★

    85219

    1/1/85219

    View full text