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A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice

¹ Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Yoshihiko Chiba, Ph.D., Department of Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. E-mail: chiba{at}hoshi.ac.jp

Interleukin-13 (IL-13) is one of the central mediators for development of airway hyperresponsiveness in asthma. The signal transducer and activation of transcription 6 (STAT6) is one of the major signal transducers activated by IL-13, and a possible involvement of IL-13/STAT6 pathway in the augmented bronchial smooth muscle (BSM) contraction has been suggested. In the present study, the effect of a novel STAT6 inhibitor, AS1517499, on the development of antigen-induced BSM hyperresponsiveness was investigated. In cultured human BSM cells, IL-13 (100 ng/ml) caused a phosphorylation of STAT6 and an up-regulation of RhoA, a monomeric GTPase responsible for Ca²⁺ sensitization of smooth muscle contraction: both events were inhibited by co-incubation with AS1517499 (100 nM). In BALB/c mice that were actively sensitized and repeatedly challenged with ovalbumin antigen, an increased IL-13 level in bronchoalveolar lavage fluids and a phosphorylation of STAT6 in bronchial tissues were observed after the last antigen challenge. These mice had an augmented BSM contractility to acetylcholine together with an up-regulation of RhoA in bronchial tissues. Intraperitoneal injections of AS1517499 (10 mg/kg) 1 hour before each ovalbumin exposure inhibited both the antigen-induced up-regulation of RhoA and BSM hyperresponsiveness, almost completely. A partial but significant inhibition of antigen-induced production of IL-13 was also found. These findings suggest that the inhibitory effects of STAT6 inhibitory agents, such as AS1517499, both on RhoA and IL-13 up-regulations might be useful for asthma treatment.

Key Words: airway hyperresponsiveness • bronchial smooth muscle • RhoA • STAT6 • AS1517499

CLINICAL RELEVANCE A signal transducer and activator of transcription 6 (STAT6) inhibitor, AS1517499, ameliorated the antigen-induced bronchial smooth muscle hyperresponsiveness by inhibiting RhoA up-regulation in bronchial smooth muscles and, at least in part, by reducing IL-13 production in the airways in mice. Both the direct and indirect effects of STAT6 inhibitory agents, such as AS1517499, on bronchial smooth muscles might be useful for the treatment of allergic bronchial asthma.