(S,S)-formoterol increases the production of IL-4 in mast cells and the airways of a murine asthma model.
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 (Fc epsilon RI) 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 PGD(2) 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 PGD(2) 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.


CONCLUSIONS
(S,S)-formoterol may exert adverse effects in asthma control by activating mast cells to produce proinflammatory mediators such as IL-4.
Abraha
Daniel
D
Division of Allergy and Immunology, Department of Pediatrics, Harbor-UCLA Medical Center, University of California, Los Angeles, Torrance, CA 90509, USA.
Cho
Seong H
SH
Agrawal
Devendra K
DK
Park
Jae M
JM
Oh
Chad K
CK
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D006636:Histamine Release / Q000187:drug effects / Q000276:immunology; D006651:Histocytochemistry; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016210:Methacholine Chloride / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D015230:Prostaglandin D2 / Q000276:immunology / Q000378:metabolism; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D001993:Bronchodilator Agents; D004983:Ethanolamines; D016210:Methacholine Chloride; D015847:Interleukin-4; D015230:Prostaglandin D2; D000068759:Formoterol Fumarate