(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 (FcepsilonRI) 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. Conclusion: ( S, S)- formoterol may exert adverse effects in asthma control by activating mast cells to produce proinflammatory mediators such as IL-4. Copyright (C) 2004 S. Karger AG, Basel.