Original Paper

(S,S)-Formoterol Increases the Production of IL-4 in Mast Cells and the Airways of a Murine Asthma Model
Daniel Abraha^a, Seong H. Cho^a, Devendra K. Agrawal^b, Jae M. Park^a, Chad K. Oh<sup>a

a</sup>Division of Allergy and Immunology, Department of Pediatrics, Harbor-UCLA Medical Center, School of Medicine, University of California, Los Angeles, Torrance, Calif. and
^bCenter for Allergy, Asthma and Immunology, Department of Medicine, Medical Microbiology and Immunology, and Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebr., USA

Address of Corresponding Author

Int Arch Allergy Immunol 2004;133:380-388 (DOI: 10.1159/000077358)

  Key Words

• (R,R)-formoterol
• (S,S)-formoterol
• Mast cells
• Interleukin-4

  Abstract

Background: Racemic formoterol is an equimolar mixture of (R,R)- and (S,S)-formoterol. Several studies have shown (S,S)-formoterol to have proinflammatory effects. We previously reported that (S)-albuterol increased the secretion of histamine and interleukin (IL)-4 in murine mast cells. We thus hypothesized that (S,S)-formoterol promotes asthma by enhancing IL-4 production in mast cells of the asthmatic airway. Methods: Murine and human mast cells were stimulated by high affinity IgE receptor (FcεRI) cross-linking or with phorbol myristate acetate/calcium ionophore A23187 (PMA/A23187). Jurkat T cells were stimulated with PMA. Cells were pretreated with either (R,R)- or (S,S)-formoterol. Ovalbumin (OVA)-sensitized BALB/c mice were pretreated with (R,R)- or (S,S)-formoterol before each intranasal OVA challenge for 10 days. Bronchoalveolar lavage fluid was obtained from the mice. The levels of IL-4, histamine and PGD₂ were measured. Early and late allergic responses (EAR and LAR, respectively) to OVA challenge and airway hyperresponsiveness (AHR) were measured. Results: (S,S)-formoterol enhanced the production of IL-4, histamine, and PGD₂ in mast cells, whereas (R,R)-formoterol had no effect. Neither (S,S)- nor (R,R)-formoterol had effect on IL-4 production in Jurkat T cells. In OVA-challenged mice, (S,S)-formoterol increased IL-4 secretion, whereas (R,R)-formoterol had no effect. Finally, (S,S)-formoterol enhanced the inflammatory changes in the peribronchial and perivascular areas without affecting EAR, LAR or AHR, whereas (R,R)-formoterol reduced EAR, LAR and AHR as well as cellular infiltration in the lung tissue of these mice. Conclusion: (S,S)-formoterol may exert adverse effects in asthma control by activating mast cells to produce proinflammatory mediators such as IL-4.

Copyright © 2004 S. Karger AG, Basel

  Author Contacts

Correspondence to: Chad K. Oh, MD
University of California, Los Angeles
UCLA School of Medicine, Harbor-UCLA Medical Center
Building N25, 1000 W. Carson Street, Torrance, CA 90509 (USA)
Tel. +1 310 222 4162, Fax +1 310 320 2271, E-Mail coh@rei.edu

  Article Information

D.A. and S.H.C. contributed equally to this work.

Received: May 20, 2003
Accepted after revision: January 9, 2004
Published online: March 17, 2004
Number of Print Pages : 9
Number of Figures : 9, Number of Tables : 0, Number of References : 27